MSC-Derived Exosomes in Posterior Segment Diseases: Comparison
Please note this is a comparison between Version 2 by Kevin Yang Wu and Version 1 by Kevin Yang Wu.

Mesenchymal stem cell (MSC) therapy has shown promise in treating ophthalmic diseases, but suboptimal biocompatibility, penetration, and delivery to the target ocular tissues remain limitations. To address these challenges, researchers have turned to MSC-derived exosomes, which possess properties similar to MSCs and can efficiently deliver therapeutic factors to ocular tissues that are typically difficult to target using conventional therapy and MSC transplantation.

Exosomes, small vesicles derived from MSCs, exhibit anti-inflammatory, anti-apoptotic, and immunomodulatory properties, making them an attractive alternative to MSCs for ocular therapy. Due to their nano-size, MSC-derived exosomes can better penetrate biological barriers, such as the blood-retinal barrier, and deliver their cargo effectively to ocular tissues. Moreover, their cargo is protected from degradation, leading to increased bioavailability [1-3]. As a result, exosomes have great potential for ocular drug-delivery applications.

Recent studies have shown that MSC-derived exosomes may offer advantages over conventional MSC-based therapies in regenerative medicine. Utilizing exosomes could eliminate the risks associated with MSC-centered therapies, such as immunological rejection, unwanted differentiation, and obstruction of small vessels through intravenous MSC injection. Avoiding these risks is critical for optimal treatment outcomes.

In this review, we focus on publications from 2017 to 2023 and discuss recent developments in the field of MSC-derived exosomes. We will explore their characteristics, functions, and potential for treating both anterior and posterior segment ocular diseases. Additionally, we examine the potential of exosome-based therapies in clinical settings while also addressing the challenges that must be overcome in preclinical studies, including in vitro and animal-based studies, to facilitate their transition to clinical trials. [4]

  • ophthalmology
  • ocular pharmacology
  • anterior segment diseases
  • posterior segment diseases
  • cell-based drug delivery systems
  • MSCs-based cell therapy
  • MSC-derived exosome
  • exosomes-baseddrug delivery
  • tissue repair and regeneration

The Use of MSC-Derived Exosomes in Posterior Segment Diseases and Uveitis

1. Age-Related Macular Degeneration

Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a prevalent eye disorder that affects individuals over 50 years old, causing vision loss and blindness in the elderly. AMD can be classified into three stages: early, intermediate, and late. Early-stage AMD presents with medium-sized drusen deposits without pigment changes or vision loss. As AMD progresses to the intermediate stage, large drusen deposits and/or pigment changes may cause mild vision loss. Late-stage AMD can be dry or wet, with wet AMD causing rapid vision decline due to fluid and blood leakage from abnormal blood vessel growth beneath the macula, known as choroidal neovascularization (CNV). Several targets exist for AMD treatment, such as reducing inflammation, inhibiting angiogenesis, and treating CNV in wet AMD. Treatment options depend on the type and severity of AMD. While dry AMD can be managed through monitoring and nutritional supplements, wet AMD typically requires frequent intravitreal injections of anti-VEGF drugs. However, not all patients respond favorably to this treatment, and vision-threatening complications such as endophthalmitis and retinal detachment may occur. MSC-derived exosomes offer potential advantages in addressing these issues. They may significantly reduce the frequency of intravitreal injections due to better biocompatibility and longer duration of action, and they have the potential to be delivered topically instead of intravitreally. Therefore, optimizing therapies that target both inflammation and neovascularization with the use of MSC-derived exosomes could provide a more effective and less burdensome treatment solution [101,102][1][2].

Hajrasouliha and colleagues were the first to demonstrate the potential therapeutic effects of exosomes in age-related macular degeneration by suppressing retinal vessel leakage and inhibiting choroidal neovascularization in 2013 [105][3]. In a subsequent study in 2018, He and colleagues investigated the effects of human umbilical cord MSC-derived exosomes on age-related macular degeneration (AMD) and the development of choroidal neovascularization (CNV) using a blue light injured human retinal pigment epithelial (RPE) cell model and a laser-induced CNV rat model [106][4]. The authors found that the MSC-derived exosomes downregulated VEGF-A expression in RPE cells and improved the histological structures of CNV for better visual function in vivo. The study suggested that MSC-derived exosomes have potential as a treatment for AMD and CNV.

Li and colleagues (2021) investigated the use of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) in vivo and in vitro to attenuate subretinal fibrosis. Laser-induced choroidal neovascularization (CNV) and subretinal fibrosis models were established in mice, and upon intravitreal injection of hUCMSC-exosomes, alleviation in subretinal fibrosis was observed in vivo. Additionally, hUCMSC-exosomes suppressed the migration of RPE cells and promoted the mesenchymal–epithelial transition via miR-27-3p. In addition, intravitreal injection of hUCMSC-exosome effectively ameliorated laser-induced CNV and subretinal fibrosis via the suppression of epithelial–mesenchymal transition (EMT) process. These studies elucidated the potential use of MSC-exosomes as an alternative treatment for wet AMD and CNV, potentially reducing the need for frequent anti-VEGF injections prescribed by ophthalmologists.

 

2. Retinitis Pigmentosa

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a hereditary disorder that causes progressive vision loss due to the degeneration of photoreceptor cells, primarily rods, resulting from genetic mutations. Unfortunately, conventional treatments for RP are limited, mainly providing symptom management, eye complication prevention, and slow disease progression. Voretigene neparvovec is a targeted gene therapy that halts and cures RP caused by the RPE65 gene mutation, present in only 0.3% to 1% of RP patients. Researchers have focused on preventing retinal degeneration by targeting the posterior eye through neuroprotective agents or mesenchymal stem cell transplantation (MSCT). These treatments aim to prevent photoreceptor death, promote its survival, and potentially regenerate functional cells and tissues [5]. [96]

In preclinical studies, mesenchymal stem cell transplantation (MSCT) and its derived exosomes (MSC-exosomes) have shown potential as treatment options for photoreceptor apoptosis in retinitis pigmentosa (RP) by preventing photoreceptor death, promoting its survival, and potentially regenerating functional cells and tissues. Deng et al. (2020) used mouse bone marrow MSCT in an N-methyl-N-nitrosourea (MNU) driven photoreceptor injury mouse model and found that MSC-exosomes were critical for preventing photoreceptor apoptosis and alleviating retinal morphological and functional degeneration [97][6]. Liu et al. (2019) treated Rd10 mutated mice with human bone marrow MSC-exosomes and observed improvements in electroretinogram (ERG) and optokinetic tracking response (OKT), as well as the inhibition of pro-inflammatory cytokine expression, indicating relief of neuroinflammation [99][7]. Similarly, Zhang et al. (2022) investigated the use of MSC-exosomes in RP and observed increased photoreceptor survival, preservation of their structure, and improved visual function. Additionally, MSC-exosomes were found to inhibit inflammation through overexpression of the miR-146a-Nr4a3 axis [98][8]. Although these preclinical studies were conducted using animal models, they elucidated the potential long-term benefits of using MSC-exosomes in the treatment of RP. However, future clinical studies are necessary to determine whether the same effects can be achieved in humans.

 

3. Diabetic Retinopathy

Diabetic Retinopathy

Diabetic retinopathy, a chronic eye condition, involves progressive damage to the blood vessels of the retina, with two types of the disease existing: non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR is characterized by vascular permeability, blockage, and the formation of various abnormalities. PDR occurs in the advanced stages of diabetic retinopathy and is caused by ongoing damage to the retinal blood vessels, which results in significant retinal ischemia. The release of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), from ischemic retinal tissue stimulates the growth of new, abnormal blood vessels, leading to vision-threatening complications such as neovascularization. Inhibiting the activity of VEGF through laser photocoagulation or intravitreal anti-VEGF injections is the primary management strategy for PDR, as these methods work by binding to VEGF and preventing it from interacting with its receptor [78][9].

Preclinical studies have investigated the therapeutic potential of MSC-exosomes to treat diabetic retinopathy (DR) and its complications. In a streptozotocin-induced diabetes mellitus (DM) rabbit model, Safwat et al. (2018) injected MSC-exosomes derived from the adipose tissue of rabbits via different routes (intravenous (IV), subconjunctival (SC), and intraocular (IO)) [99][7]. Retinal regeneration was observed at 12 weeks post-administration, with the IV route resulting in irregular ganglionic layer and increased retinal thickness, SC administration leading to well-defined layers, and IO administration resulting in morphologically and functionally analogous layers to those of a normal retina. The role of micRNA-222 in DR was also explored, with the findings showing that its underexpression in hyperglycemic conditions resulted in increased retinal damage and hemorrhage. However, this damage was ameliorated through MSC-exosomal transfer of micRNA-222 [79][10]. Additionally, Zhang et al. (2019) investigated the role of miR-126 transfer via human umbilical cord mesenchymal stem cell (MSC)-derived exosomes (hUCMSC-Exos) in regulating hyperglycemia-induced retinal inflammation [7][11]. The administration of hUCMSC-exosomes effectively reversed inflammation in diabetic rats, with hUCMSC-exosomes overexpressing miR-126 more successfully suppressing inflammation compared to control hUCMSC-exosomes. This highlights the key role of miR-126 in attenuating DR.

Studies have identified individual microRNAs involved in the amelioration of DR by MSC-exosomes. Li et al. (2021) showed the potential of bone marrow mesenchymal stem cell (BMSC)-induced exosomal microRNA-486-3p (miR-486-3p) in treating DR in mice [100][12]. Histological analysis of Muller cells injected with streptozotocin (STZ) confirmed DR pathology, with upregulated Toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB). Exposure to BMSC-exosomes in vitro promoted Muller cell proliferation and inhibited inflammation, oxidative stress, and apoptosis. Upregulating miR-486-3p or downregulating TLR4 further inhibited oxidative stress, inflammation, and apoptosis, indicating that miR-486-3p targets TLR4. Li et al. (2021) then demonstrated the role of microRNA-17-3p in targeting the signal transducer and activator of transcription 1 (STAT1) in a DR mouse model [101][1]. An overexpression of miR-17-3p in hUCMSC-exosomes decreased STAT1 expression, while a depletion of miR-17-3p in exosomes exerted an inverse effect. Overall, injection of MSC-exosomes overexpressing miR-17-3p reduced blood glucose and HbA1c, increased body weight and Hb content, decreased inflammatory factors and VEGF, alleviated oxidative injury, and inhibited retinal cell apoptosis in DR mice through the inhibition of STAT1.

Gu and colleagues (2022) investigated the use of bone marrow mesenchymal stem cell (BMSC) exosomal miR-146a to reduce inflammation in DR mice [102][2]. The researchers found that exposing microglial cells of DR mice to BMSC exosomal miR-146a reduced levels of proliferating cell antigen and B-cell lymphoma-2, as well as inflammatory cytokines TNF-α, IL-1β, and IL-6. The study also showed an inverse association between miR-146a and TLR4, as overexpression of TLR4 reversed the effects of miR-146a on the proliferation, apoptosis, and inflammation of microglia. Another study conducted by Ebrahim and colleagues (2022) investigated the Wnt/b-catenin signaling pathway in DR using rat bone marrow-derived mesenchymal stem cell exosomes (BMMSCs) [103][13]. The researchers treated rats with STZ-induced DR with intravitreal administration of BMMSC-exosomes to block the wnt/b-catenin pathway. They found that this treatment resulted in a significant decrease in retinal mRNA markers indicative of oxidative stress, inflammation, and angiogenesis and vascular leakage in DR compared to diabetic controls. This effect was achieved by targeting the miR-129–5p and miR-34a exosomal microRNA.

Cao and colleagues (2021) investigated the involvement of long non-coding RNA (lncRNAs) small nucleolar RNA host gene (SNHG7) in DR pathogenesis [104][14]. They used human retinal microvascular endothelial cells (HRMECs) treated with high glucose (HG) to establish a DR cell model. Their findings suggest that MSC-exosomal lncRNA SNHG7 downregulates miR-34a-5p and inhibits hyperglycemia-induced endothelial–mesenchymal transition (EndMT) and tube formation of HRMECs. Overexpression of miR-34a-5p reversed these benefits, while knockdown of miR-34a-5p repressed HG-induced EndMT and tube formation. Overall, these results highlight the potential of MSC-exosomal lncRNA SNHG7 in suppressing EndMT and tube formation in HRMECs via miR-34a-5p/XBP1 downregulation.

 

4. Retinal Ischemia

Retinal Ischemia

Retinal ischemia is a condition caused by insufficient blood flow to the retina, leading to a lack of oxygen and nutrients and potential vision loss. Both systemic and ocular conditions can contribute to its development. Systemic causes include diabetes mellitus, hypertension, and blood dyscrasias, while ocular causes include retinal vascular occlusions and carotid artery stenosis. Inflammatory and degenerative eye diseases can also induce retinal ischemia by compromising ocular circulation. Treatment options depend on the underlying cause, but anti-VEGF medications are commonly prescribed to prevent abnormal blood vessel growth in the retina.

Several studies have investigated the potential of MSC-exosomes in treating retinal ischemic injuries. Mosseiev et al. (2017) demonstrated the protective effect of human mesenchymal stem cells (hMSCs) administered intravitreally in the murine model. The study induced oxygen-induced retinopathy in two groups of mice, followed by administration of saline and MSC-exosomes, respectively. Results indicated that hMSC-exosomes significantly reduced retinal thinning and neovascularization, suggesting the therapeutic effect of paracrine factors and miRNAs. In a laser-induced injury and ischemia model, Yu et al. (2016) also found that intravitreal injection of adipose-derived and human umbilical cord-derived MSC-exosomes reduced damage, inhibited apoptosis, and suppressed inflammatory responses in mice. Moreover, the downregulation of monocyte chemotactic protein (MCP)-1 in the retina suggests that MSC-exosomes may ameliorate laser-induced retinal injury. These studies demonstrate promising results, and the use of MSC-exosomes could potentially be extended to other ischemic retinal diseases, such as retinopathy of prematurity, ocular ischemic syndrome, and retinal vein and artery occlusion.

Mathew and colleagues (2019) investigated the neuroprotective effects of mesenchymal stem cell (MSC)-exosomes in retinal ischemia. They used an in vitro oxygen-glucose deprivation (OGD) model of retinal ischemia with R28 cell line derived from rats and found that MSC-exosomes reduced cell death, attenuated loss of cell proliferation, and decreased neuroinflammation and apoptosis in the rat model when injected into the vitreous humor 24 h post-ischemia development. MSC-exosomes were present in the vitreous humor for four weeks after intravitreal administration [107][15]. Yu and colleagues (2022) explored the neuroprotective effects of human gingival MSCs (hGMSC) derived exosomes in retinal ischemia-reperfusion injury [108][16]. They injected hGMSC-exosomes into the vitreous of mice and found that the injection of exosomes transfected with siRNA-maternally expressed gene 3 (siRNA-MEG3) that were stimulated by TNF-α (TG-exos) significantly reduced inflammation and cell loss compared to unstimulated exosomes (G-exos) in mice with retinal ischemia. Furthermore, miR-21-5p acted as a crucial factor in TG-exos for neuroprotection and anti-inflammation. These findings suggest that MSC-exosomes have potential as a therapeutic option for retinal ischemic injuries.

Finally, Ma and colleagues (2020) investigated the potential therapeutic effects of using rat bone marrow-derived MSC-exosomes in a rat retinal detachment model [109][17]. The subretinal administration of MSC-exosomes at the time of retinal separation reduced the expression of proinflammatory cytokines at day seven and suppressed photoreceptor cell apoptosis, resulting in the maintenance of normal retinal structure. This study highlights the potential therapeutic effects of MSC-exosomes on retinal ischemia secondary to retinal detachment.

 

5. Uveitis

Uveitis

Uveitis is an ocular inflammation that affects the uvea, which encompasses the iris, ciliary body, and choroid. The type of uveitis depends on the part of the eye involved, with anterior, intermediate, posterior, and panuveitic forms being the most common types. The causes of uveitis can be diverse, with non-infectious autoimmune or idiopathic sources being the most prevalent, while infectious causes are typically less frequent but more severe. Non-infectious anterior uveitis is usually treated with glucocorticoid steroids, either topically or orally, and sometimes in combination with non-steroidal therapies. However, posterior uveitis presents a greater challenge, as topical eye drops cannot reach the critical posterior segments of the eye, including the macula, optic nerve, and retinal vessels, where rapid vision loss and blindness can occur. In these instances, more invasive administration methods, such as periocular or intravitreal injection, are often required. The use of MSC-derived exosomes as a drug-delivery system is promising, as they may effectively penetrate barriers and protect their cargo from degradation, leading to increased bioavailability. This concept has been previously addressed in the article, illustrated in Figure 3.

In 2014, Oh and colleagues demonstrated the potential benefits of using mesenchymal stem cells (MSCs) to prevent experimental autoimmune uveitis (EAU) in mice. The administration of intraperitoneal hMSCs resulted in a reduction in proinflammatory cytokines in the eye and a marked suppression of Th1 and Th17 cells in draining lymph nodes, protecting the retina and attenuating EAU. More recently, Zhang et al. (2018) investigated the efficacy of human umbilical cord-derived MSC-exosomes in treating large and refractory macular holes (MHs) in seven patients who underwent vitrectomy and internal limiting membrane peeling. Six of the MHs closed post-treatment, indicating the potential benefits of MSC and MSC-exosome therapy in promoting functional and anatomic recovery from MH. Compared to MSCT therapy, MSC-exosome therapy was found to be safer and easier to administer due to its lower risk of developing proliferations and immune responses, and the small size of MSCs allows for various administration routes. However, a lack of a control group and limited patient numbers prevented conclusions about the superiority of MSC-exosome therapy over MSCT treatment for MH closure.

Recent studies have focused on exploring MSC-exosomes as potential therapeutic agents for EAU, since their therapeutic effects are mediated via the transport and transfer of exosomes containing various miRNAs. Shigemoto-Kuroda et al. (2017) investigated the use of MSC-exosomes for T1D and EAU by harvesting exosomes from human bone marrow MSCs and administering them intravenously into established mouse models. The study found that MSC-exosomes prevented the onset of T1D and EAU by inhibiting the activation of antigen-presenting cells and suppressing the activation of Th1 and Th17 cells. Similar findings were reported by Bai et al. (2017) when exploring the potential therapeutic effects of human umbilical cord-derived MSC-exosomes on EAU. In vivo administration of MSC-exosomes demonstrated a milder development of EAU compared to control rats, and in vitro assays demonstrated a marked reduction in the intensity of EAU following MSC-exosomes administration. MSC-exosomes effectively inhibited the migration of CD4+T cells, neutrophils, NK cells, and macrophage cells, reduced the percentage of CD4+IFN-γ+ and CD4+IL-17+ cells in the retina, and reduced unchecked inflammation. Although MSC-exosomes treatment reduced the concentration of Tregs, the reduction was not significant enough to eliminate the impending beneficial role of Tregs in the suppression of EAU. Overall, preclinical studies suggest that MSC-exosomes could serve as a potential treatment for T1D and EAU, reducing the need for conventional treatments such as topical steroids and systemic immunosuppressants.

Xie et al. (2018) conducted a study to investigate the effects of MSC-exosomes on EAU in a rat model. The experimental group received periocular injection of MSC-exosomes while the control group received phosphate buffer [117][18]. The study observed that CD68 cell expression was significantly lower in the experimental group, even 15 days after administration of MSC-exosomes. The retinal pathological score was also significantly lower in the experimental group, along with a decrease in the number of Th1, Th17, and Tregs. The study also showed that the experimental group had better retinal function than the control group 15 days post MSC-exosomes administration. Similarly, Yongtao et al. (2021) confirmed the therapeutic effects of MSC-exosomes on EAU through intravenous injection of hUCMSCs in mice [119]. In this study, the treatment group showed significantly lower inflammation and pathological scores compared to the control group. There was also a decrease in the number of Th1 and Th17 cells, as well as reduced proliferation of other T cell subtypes in the experimental group. Based on these findings, Yongtao et al. (2022) conducted a subsequent study to investigate the potential therapeutic role of IL-10-overexpressing MSC-exosomes on EAU [118][19]. This study revealed that IL-10-overexpressing MSC-exosomes effectively suppressed the proliferation and differentiation of Th1 and Th17 cells with increased Treg cells in the spleen and DLN. Overall, these preclinical studies suggest that MSC-exosomes have the potential to be a novel therapy for treating EAU.

Li and colleagues (2022) investigated the use of Rapamycin loaded MSC-exosomes (Rapa-MSC exosomes) as a conjugate therapy for EAU and ocular complications caused by frequent intravitreal injections, given the successful penetration of MSC-exosomes into the eye. In mice with EAU, Rapa-MSC exosomes were found to significantly reduce ocular inflammatory cell infiltration, protect the retinal structure and improve drug delivery of Rapamycin into the eye within 24 h of subconjunctival injection. This study highlights the potential of MSC-exosomes in improving drug delivery and efficacy in the eye [19]. [118]

 

6. Idiopathic Macular Hole

Idiopathic Macular Hole

An idiopathic macular hole, a tear in the center of the retina caused by pathological vitreoretinal traction, can result in central vision loss or distortion. Treatment options depend on the severity of the condition, with stage 2 or above requiring a surgical intervention called pars plana vitrectomy (PPV). However, PPV is invasive and carries several risks, including tearing or detachment of the retina, increased eye pressure, reinfection, and permanent vision loss. Additionally, the postoperative period demands strict compliance with a prone position for over a week, which can be uncomfortable for patients [110][20].

Intravitreal ocriplasmin provides a less invasive treatment option for macular holes, but it still carries certain risks associated with the injection and the drug itself. Risks may include lens subluxation or phacodonesis, dyschromatopsia, transient changes in the electroretinogram, retinal tear or detachment, and decreased visual acuity [111][21].

Zhang et al. (2018) investigated the efficacy of human umbilical cord-derived MSC-exosomes to treat large and refractory macular holes (MHs). In a study of seven patients, all underwent vitrectomy and internal limiting membrane peeling, with two receiving MSCT therapy and five receiving MSC-exosome treatment. Six of the MHs closed post-treatment, while one remained flat-open. MSC-exosome therapy was found to be safer and easier to administer than MSCT therapy due to its lower risk of developing proliferations and immune responses, as well as the small size of MSC allowing for various administration routes. However, a lack of a control group and a limited number of patients did not allow for conclusions about the superiority of MSC-exosome therapy over MSCT treatment for MH closure. Nonetheless, the findings indicate the potential benefits of MSC and MSC-exosome therapy in promoting functional and anatomic recovery from MH.

 

[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142]

References

  1. Niamprem, P.; Srinivas, S.P.; Tiyaboonchai, W. Penetration of Nile Red-Loaded Nanostructured Lipid Carriers (NLCs) across the Porcine Cornea. Colloids Surf. B Biointerfaces 2019, 176, 371–378. [Google Scholar] [CrossRef] [PubMed]Li, W.; Jin, L.; Cui, Y.; Xie, N. Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomal MicroRNA-17-3p Ameliorates Inflammatory Reaction and Antioxidant Injury of Mice with Diabetic Retinopathy via Targeting STAT1. Int. Immunopharmacol. 2021, 90, 107010.
  2. Blass, S.; Teubl, B.; Fröhlich, E.; Meindl, C.; Rabensteiner, D.F.; Trummer, G.; Schmut, O.; Zimmer, A.; Roblegg, E. Permeability Studies on the Ocular Absorbance of Nanostructured Materials Across the Cornea. Sci. Pharm. 2010, 78, 678. [Google Scholar] [CrossRef][Green Version]Gu, C.; Zhang, H.; Zhao, S.; He, D.; Gao, Y. Mesenchymal Stem Cell Exosomal MiR-146a Mediates the Regulation of the TLR4/MyD88/NF-ΚB Signaling Pathway in Inflammation Due to Diabetic Retinopathy. Comput. Math. Methods Med. 2022, 2022, 3864863.
  3. Mohammadpour, M.; Hashemi, H.; Jabbarvand, M.; Delrish, E. Penetration of Silicate Nanoparticles into the Corneal Stroma and Intraocular Fluids. Cornea 2014, 33, 738. [Google Scholar] [CrossRef]Hajrasouliha, A.R.; Jiang, G.; Lu, Q.; Lu, H.; Kaplan, H.J.; Zhang, H.-G.; Shao, H. Exosomes from Retinal Astrocytes Contain Antiangiogenic Components That Inhibit Laser-Induced Choroidal Neovascularization. J. Biol. Chem. 2013, 288, 28058–28067.
  4. Yu, B.; Shao, H.; Su, C.; Jiang, Y.; Chen, X.; Bai, L.; Zhang, Y.; Li, Q.; Zhang, X.; Li, X. Exosomes Derived from MSCs Ameliorate Retinal Laser Injury Partially by Inhibition of MCP-1. Sci. Rep. 2016, 6, 34562. [Google Scholar] [CrossRef] [PubMed][Green Version]He, G.-H.; Zhang, W.; Ma, Y.-X.; Yang, J.; Chen, L.; Song, J.; Chen, S. Mesenchymal Stem Cells-Derived Exosomes Ameliorate Blue Light Stimulation in Retinal Pigment Epithelium Cells and Retinal Laser Injury by VEGF-Dependent Mechanism. Int. J. Ophthalmol. 2018, 11, 559–566.
  5. Yu, B.; Li, X.-R.; Zhang, X.-M. Mesenchymal Stem Cell-Derived Extracellular Vesicles as a New Therapeutic Strategy for Ocular Diseases. World J. Stem Cells 2020, 12, 178–187. [Google Scholar] [CrossRef] [PubMed]Cuenca, N.; Fernández-Sánchez, L.; Campello, L.; Maneu, V.; De la Villa, P.; Lax, P.; Pinilla, I. Cellular Responses Following Retinal Injuries and Therapeutic Approaches for Neurodegenerative Diseases. Prog. Retin. Eye Res. 2014, 43, 17–75.
  6. Cui, Y.; Liu, C.; Huang, L.; Chen, J.; Xu, N. Protective Effects of Intravitreal Administration of Mesenchymal Stem Cell-Derived Exosomes in an Experimental Model of Optic Nerve Injury. Exp. Cell Res. 2021, 407, 112792. [Google Scholar] [CrossRef] [PubMed]Deng, C.-L.; Hu, C.-B.; Ling, S.-T.; Zhao, N.; Bao, L.-H.; Zhou, F.; Xiong, Y.-C.; Chen, T.; Sui, B.-D.; Yu, X.-R.; et al. Photoreceptor Protection by Mesenchymal Stem Cell Transplantation Identifies Exosomal MiR-21 as a Therapeutic for Retinal Degeneration. Cell Death Differ. 2021, 28, 1041–1061.
  7. Zhang, W.; Wang, Y.; Kong, Y. Exosomes Derived from Mesenchymal Stem Cells Modulate MiR-126 to Ameliorate Hyperglycemia-Induced Retinal Inflammation Via Targeting HMGB1. Investig. Opthalmol. Vis. Sci. 2019, 60, 294. [Google Scholar] [CrossRef][Green Version]Safwat, A.; Sabry, D.; Ragiae, A.; Amer, E.; Mahmoud, R.H.; Shamardan, R.M. Adipose mesenchymal stem cells–derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits. J. Circ. Biomark. 2018, 7, 1849454418807827.
  8. Xu, H.-K.; Chen, L.-J.; Zhou, S.-N.; Li, Y.-F.; Xiang, C. Multifunctional Role of MicroRNAs in Mesenchymal Stem Cell-Derived Exosomes in Treatment of Diseases. World J. Stem Cells 2020, 12, 1276–1294. [Google Scholar] [CrossRef]Zhang, J.; Li, P.; Zhao, G.; He, S.; Xu, D.; Jiang, W.; Peng, Q.; Li, Z.; Xie, Z.; Zhang, H.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Retina in a Mouse Model of Retinitis Pigmentosa by Anti-Inflammation through MiR-146a-Nr4a3 Axis. Stem Cell Res. Ther. 2022, 13, 394.
  9. Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Théry, C. Specificities of Secretion and Uptake of Exosomes and Other Extracellular Vesicles for Cell-to-Cell Communication. Nat. Cell Biol. 2019, 21, 9–17. [Google Scholar] [CrossRef]Mead, B.; Ahmed, Z.; Tomarev, S. Mesenchymal Stem Cell–Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. Investig. Opthalmol. Vis. Sci. 2018, 59, 5473.
  10. Van Niel, G.; D’Angelo, G.; Raposo, G. Shedding Light on the Cell Biology of Extracellular Vesicles. Nat. Rev. Mol. Cell Biol. 2018, 19, 213–228. [Google Scholar] [CrossRef]Mead, B.; Amaral, J.; Tomarev, S. Mesenchymal Stem Cell–Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Investig. Opthalmol. Vis. Sci. 2018, 59, 702.
  11. Xu, M.; Ji, J.; Jin, D.; Wu, Y.; Wu, T.; Lin, R.; Zhu, S.; Jiang, F.; Ji, Y.; Bao, B.; et al. The Biogenesis and Secretion of Exosomes and Multivesicular Bodies (MVBs): Intercellular Shuttles and Implications in Human Diseases. Genes Dis. 2022, S2352304222000976. [Google Scholar] [CrossRef]Zhang, W.; Wang, Y.; Kong, Y. Exosomes Derived from Mesenchymal Stem Cells Modulate MiR-126 to Ameliorate Hyperglycemia-Induced Retinal Inflammation Via Targeting HMGB1. Investig. Opthalmol. Vis. Sci. 2019, 60, 294.
  12. Wu, H.; Turner, C.; Gardner, J.; Temple, B.; Brennwald, P. The Exo70 Subunit of the Exocyst Is an Effector for Both Cdc42 and Rho3 Function in Polarized Exocytosis. Mol. Biol. Cell 2010, 21, 430–442. [Google Scholar] [CrossRef] [PubMed][Green Version]Li, W.; Jin, L.; Cui, Y.; Nie, A.; Xie, N.; Liang, G. Bone Marrow Mesenchymal Stem Cells-Induced Exosomal MicroRNA-486-3p Protects against Diabetic Retinopathy through TLR4/NF-ΚB Axis Repression. J. Endocrinol. Investig. 2021, 44, 1193–1207.
  13. Hung, M.E.; Leonard, J.N. Stabilization of Exosome-Targeting Peptides via Engineered Glycosylation. J. Biol. Chem. 2015, 290, 8166–8172. [Google Scholar] [CrossRef][Green Version]Ebrahim, N.; El-Halim, H.E.A.; Helal, O.K.; El-Azab, N.E.-E.; Badr, O.A.M.; Hassouna, A.; Saihati, H.A.A.; Aborayah, N.H.; Emam, H.T.; El-wakeel, H.S.; et al. Effect of Bone Marrow Mesenchymal Stem Cells-Derived Exosomes on Diabetes-Induced Retinal Injury: Implication of Wnt/b-Catenin Signaling Pathway. Biomed. Pharmacother. 2022, 154, 113554.
  14. McKelvey, K.J.; Powell, K.L.; Ashton, A.W.; Morris, J.M.; McCracken, S.A. Exosomes: Mechanisms of Uptake. J. Circ. Biomark. 2015, 4, 7. [Google Scholar] [CrossRef][Green Version]Cao, X.; Xue, L.-D.; Di, Y.; Li, T.; Tian, Y.-J.; Song, Y. MSC-Derived Exosomal LncRNA SNHG7 Suppresses Endothelial-Mesenchymal Transition and Tube Formation in Diabetic Retinopathy via MiR-34a-5p/XBP1 Axis. Life Sci. 2021, 272, 119232.
  15. Bian, B.; Zhao, C.; He, X.; Gong, Y.; Ren, C.; Ge, L.; Zeng, Y.; Li, Q.; Chen, M.; Weng, C.; et al. Exosomes Derived from Neural Progenitor Cells Preserve Photoreceptors during Retinal Degeneration by Inactivating Microglia. J. Extracell. Vesicles 2020, 9, 1748931. [Google Scholar] [CrossRef] [PubMed][Green Version]Mathew, B.; Ravindran, S.; Liu, X.; Torres, L.; Chennakesavalu, M.; Huang, C.-C.; Feng, L.; Zelka, R.; Lopez, J.; Sharma, M.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles and Retinal Ischemia-Reperfusion. Biomaterials 2019, 197, 146–160.
  16. Yeo, R.W.Y.; Lai, R.C.; Zhang, B.; Tan, S.S.; Yin, Y.; Teh, B.J.; Lim, S.K. Mesenchymal Stem Cell: An Efficient Mass Producer of Exosomes for Drug Delivery. Adv. Drug Deliv. Rev. 2013, 65, 336–341. [Google Scholar] [CrossRef]Yu, Z.; Wen, Y.; Jiang, N.; Li, Z.; Guan, J.; Zhang, Y.; Deng, C.; Zhao, L.; Zheng, S.G.; Zhu, Y.; et al. TNF-α Stimulation Enhances the Neuroprotective Effects of Gingival MSCs Derived Exosomes in Retinal Ischemia-Reperfusion Injury via the MEG3/MiR-21a-5p Axis. Biomaterials 2022, 284, 121484.
  17. Liu, X.; Hu, L.; Liu, F. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Cell-Free Therapy of Ocular Diseases. Extracell. Vesicles Circ. Nucleic Acids 2022, 3, 102–117. [Google Scholar] [CrossRef]Ma, M.; Li, B.; Zhang, M.; Zhou, L.; Yang, F.; Ma, F.; Shao, H.; Li, Q.; Li, X.; Zhang, X. Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes on Retinal Detachment. Exp. Eye Res. 2020, 191, 107899.
  18. Samaeekia, R.; Rabiee, B.; Putra, I.; Shen, X.; Park, Y.J.; Hematti, P.; Eslani, M.; Djalilian, A.R. Effect of Human Corneal Mesenchymal Stromal Cell-Derived Exosomes on Corneal Epithelial Wound Healing. Investig. Opthalmol. Vis. Sci. 2018, 59, 5194. [Google Scholar] [CrossRef][Green Version]Xie, R.; Bai, L.; Yang, J.; Li, Y.; Dong, L.; Ma, F.; Li, X.; Zhang, X. Effects of rat mesenchymal stem cell-derived exosomes on rat experimental autoimmune uveitis. Chin. J. Ocul. Fundus Dis. 2018, 34, 562–567.
  19. Zhang, Z.; Mugisha, A.; Fransisca, S.; Liu, Q.; Xie, P.; Hu, Z. Emerging Role of Exosomes in Retinal Diseases. Front. Cell Dev. Biol. 2021, 9, 643680. [Google Scholar] [CrossRef]Li, Y.; Ren, X.; Zhang, Z.; Duan, Y.; Li, H.; Chen, S.; Shao, H.; Li, X.; Zhang, X. Effect of Small Extracellular Vesicles Derived from IL-10-Overexpressing Mesenchymal Stem Cells on Experimental Autoimmune Uveitis. Stem Cell Res. Ther. 2022, 13, 100.
  20. Boukouris, S.; Mathivanan, S. Exosomes in Bodily Fluids Are a Highly Stable Resource of Disease Biomarkers. PROTEOMICS Clin. Appl. 2015, 9, 358–367. [Google Scholar] [CrossRef][Green Version]Dervenis, N.; Dervenis, P.; Sandinha, T.; Murphy, D.C.; Steel, D.H. Intraocular Tamponade Choice with Vitrectomy and Internal Limiting Membrane Peeling for Idiopathic Macular Hole: A Systematic Review and Meta-Analysis. Ophthalmol. Retina 2022, 6, 457–468.
  21. Chen, T.S.; Lai, R.C.; Lee, M.M.; Choo, A.B.H.; Lee, C.N.; Lim, S.K. Mesenchymal Stem Cell Secretes Microparticles Enriched in Pre-MicroRNAs. Nucleic Acids Res. 2010, 38, 215–224. [Google Scholar] [CrossRef] [PubMed][Green Version]Muqit, M.M.K.; Hamilton, R.; Ho, J.; Tucker, S.; Buck, H. Intravitreal Ocriplasmin for the Treatment of Vitreomacular Traction and Macular Hole- A Study of Efficacy and Safety Based on NICE Guidance. PLoS ONE 2018, 13, e0197072.
  22. Lai, R.C.; Tan, S.S.; Teh, B.J.; Sze, S.K.; Arslan, F.; de Kleijn, D.P.; Choo, A.; Lim, S.K. Proteolytic Potential of the MSC Exosome Proteome: Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome. Int. J. Proteomics 2012, 2012, 971907. [Google Scholar] [CrossRef] [PubMed][Green Version]
  23. Glover, K.; Mishra, D.; Singh, T.R.R. Epidemiology of Ocular Manifestations in Autoimmune Disease. Front. Immunol. 2021, 12, 744396. [Google Scholar] [CrossRef] [PubMed]
  24. Seo, Y.; Kim, H.-S.; Hong, I.-S. Stem Cell-Derived Extracellular Vesicles as Immunomodulatory Therapeutics. Available online: https://www.hindawi.com/journals/sci/2019/5126156/ (accessed on 14 February 2023).
  25. Kuriyan, A.E.; Albini, T.A.; Townsend, J.H.; Rodriguez, M.; Pandya, H.K.; Leonard, R.E.; Parrott, M.B.; Rosenfeld, P.J.; Flynn, H.W.; Goldberg, J.L. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. N. Engl. J. Med. 2017, 376, 1047–1053. [Google Scholar] [CrossRef][Green Version]
  26. Sun, H.; Pratt, R.E.; Hodgkinson, C.P.; Dzau, V.J. Sequential Paracrine Mechanisms Are Necessary for the Therapeutic Benefits of Stem Cell Therapy. Am. J. Physiol. Cell Physiol. 2020, 319, C1141–C1150. [Google Scholar] [CrossRef]
  27. Zhang, Y.; Liu, Y.; Liu, H.; Tang, W.H. Exosomes: Biogenesis, Biologic Function and Clinical Potential. Cell Biosci. 2019, 9, 19. [Google Scholar] [CrossRef]
  28. Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering Exosomes for Targeted Drug Delivery. Theranostics 2021, 11, 3183–3195. [Google Scholar] [CrossRef]
  29. Seyedrazizadeh, S.-Z.; Poosti, S.; Nazari, A.; Alikhani, M.; Shekari, F.; Pakdel, F.; Shahpasand, K.; Satarian, L.; Baharvand, H. Extracellular Vesicles Derived from Human ES-MSCs Protect Retinal Ganglion Cells and Preserve Retinal Function in a Rodent Model of Optic Nerve Injury. Stem Cell Res. Ther. 2020, 11, 203. [Google Scholar] [CrossRef]
  30. Pan, D.; Chang, X.; Xu, M.; Zhang, M.; Zhang, S.; Wang, Y.; Luo, X.; Xu, J.; Yang, X.; Sun, X. UMSC-Derived Exosomes Promote Retinal Ganglion Cells Survival in a Rat Model of Optic Nerve Crush. J. Chem. Neuroanat. 2019, 96, 134–139. [Google Scholar] [CrossRef]
  31. Chen, C.C.; Liu, L.; Ma, F.; Wong, C.W.; Guo, X.E.; Chacko, J.V.; Farhoodi, H.P.; Zhang, S.X.; Zimak, J.; Ségaliny, A.; et al. Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro. Cell. Mol. Bioeng. 2016, 9, 509–529. [Google Scholar] [CrossRef][Green Version]
  32. Li, C.; Qin, S.; Wen, Y.; Zhao, W.; Huang, Y.; Liu, J. Overcoming the Blood-Brain Barrier: Exosomes as Theranostic Nanocarriers for Precision Neuroimaging. J. Control. Release Off. J. Control. Release Soc. 2022, 349, 902–916. [Google Scholar] [CrossRef] [PubMed]
  33. Heidarzadeh, M.; Gürsoy-Özdemir, Y.; Kaya, M.; Eslami Abriz, A.; Zarebkohan, A.; Rahbarghazi, R.; Sokullu, E. Exosomal Delivery of Therapeutic Modulators through the Blood–Brain Barrier; Promise and Pitfalls. Cell Biosci. 2021, 11, 142. [Google Scholar] [CrossRef] [PubMed]
  34. Elliott, R.O.; He, M. Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery. Pharmaceutics 2021, 13, 122. [Google Scholar] [CrossRef] [PubMed]
  35. Tang, Y.; Zhou, Y.; Li, H.-J. Advances in Mesenchymal Stem Cell Exosomes: A Review. Stem Cell Res. Ther. 2021, 12, 71. [Google Scholar] [CrossRef] [PubMed]
  36. Jia, Y.; Ni, Z.; Sun, H.; Wang, C. Microfluidic Approaches Toward the Isolation and Detection of Exosome Nanovesicles. IEEE Access 2019, 7, 45080–45098. [Google Scholar] [CrossRef]
  37. Zhang, Y.; Bi, J.; Huang, J.; Tang, Y.; Du, S.; Li, P. Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications. Int. J. Nanomed. 2020, 15, 6917–6934. [Google Scholar] [CrossRef]
  38. Moisseiev, E.; Anderson, J.D.; Oltjen, S.; Goswami, M.; Zawadzki, R.J.; Nolta, J.A.; Park, S.S. Protective Effect of Intravitreal Administration of Exosomes Derived from Mesenchymal Stem Cells on Retinal Ischemia. Curr. Eye Res. 2017, 42, 1358–1367. [Google Scholar] [CrossRef][Green Version]
  39. Zhou, T.; He, C.; Lai, P.; Yang, Z.; Liu, Y.; Xu, H.; Lin, X.; Ni, B.; Ju, R.; Yi, W.; et al. MiR-204–Containing Exosomes Ameliorate GVHD-Associated Dry Eye Disease. Sci. Adv. 2022, 8, eabj9617. [Google Scholar] [CrossRef]
  40. Wang, J.; Chen, D.; Ho, E.A. Challenges in the Development and Establishment of Exosome-Based Drug Delivery Systems. J. Control. Release 2021, 329, 894–906. [Google Scholar] [CrossRef]
  41. Sun, Y.; Liu, G.; Zhang, K.; Cao, Q.; Liu, T.; Li, J. Mesenchymal Stem Cells-Derived Exosomes for Drug Delivery. Stem Cell Res. Ther. 2021, 12, 561. [Google Scholar] [CrossRef]
  42. Yu, M.; Liu, W.; Li, J.; Lu, J.; Lu, H.; Jia, W.; Liu, F. Exosomes Derived from Atorvastatin-Pretreated MSC Accelerate Diabetic Wound Repair by Enhancing Angiogenesis via AKT/ENOS Pathway. Stem Cell Res. Ther. 2020, 11, 350. [Google Scholar] [CrossRef]
  43. Wilson, S.E. Corneal Wound Healing. Exp. Eye Res. 2020, 197, 108089. [Google Scholar] [CrossRef]
  44. Du, Y.; SundarRaj, N.; Funderburgh, M.L.; Harvey, S.A.; Birk, D.E.; Funderburgh, J.L. Secretion and Organization of a Cornea-like Tissue In Vitro by Stem Cells from Human Corneal Stroma. Investig. Ophthalmol. Vis. Sci. 2007, 48, 5038–5045. [Google Scholar] [CrossRef] [PubMed]
  45. Sharif, Z.; Sharif, W. Corneal Neovascularization: Updates on Pathophysiology, Investigations & Management. Rom. J. Ophthalmol. 2019, 63, 15–22. [Google Scholar] [PubMed]
  46. Yu, B.; Zhang, X.; Li, X. Exosomes Derived from Mesenchymal Stem Cells. Int. J. Mol. Sci. 2014, 15, 4142–4157. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Phinney, D.G.; Pittenger, M.F. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells 2017, 35, 851–858. [Google Scholar] [CrossRef][Green Version]
  48. Tao, H.; Chen, X.; Cao, H.; Zheng, L.; Li, Q.; Zhang, K.; Han, Z.; Han, Z.-C.; Guo, Z.; Li, Z.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Corneal Wound Repair. Stem Cells Int. 2019, 2019, 5738510. [Google Scholar] [CrossRef][Green Version]
  49. Yu, Z.; Hao, R.; Du, J.; Wu, X.; Chen, X.; Zhang, Y.; Li, W.; Gu, Z.; Yang, H. A Human Cornea-on-a-Chip for the Study of Epithelial Wound Healing by Extracellular Vesicles. iScience 2022, 25, 104200. [Google Scholar] [CrossRef]
  50. Liu, X.; Li, X.; Wu, G.; Qi, P.; Zhang, Y.; Liu, Z.; Li, X.; Yu, Y.; Ye, X.; Li, Y.; et al. Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Deliver MiR-21 to Promote Corneal Epithelial Wound Healing through PTEN/PI3K/Akt Pathway. Stem Cells Int. 2022, 2022, 1252557. [Google Scholar] [CrossRef]
  51. Ma, S.; Yin, J.; Hao, L.; Liu, X.; Shi, Q.; Diao, Y.; Yu, G.; Liu, L.; Chen, J.; Zhong, J. Exosomes from Human Umbilical Cord Mesenchymal Stem Cells Treat Corneal Injury via Autophagy Activation. Front. Bioeng. Biotechnol. 2022, 10, 879192. [Google Scholar] [CrossRef]
  52. Shen, T.; Zheng, Q.-Q.; Shen, J.; Li, Q.-S.; Song, X.-H.; Luo, H.-B.; Hong, C.-Y.; Yao, K. Effects of Adipose-Derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis. Chin. Med. J. 2018. Available online: https://mednexus.org/doi/full/10.4103/0366-6999.226889 (accessed on 12 February 2023). [CrossRef] [PubMed]
  53. Du, Y.; Funderburgh, M.L.; Mann, M.M.; SundarRaj, N.; Funderburgh, J.L. Multipotent Stem Cells in Human Corneal Stroma. Stem Cells 2005, 23, 1266–1275. Available online: https://academic.oup.com/stmcls/article/23/9/1266/6399870 (accessed on 12 February 2023). [CrossRef] [PubMed][Green Version]
  54. Du, Y.; Carlson, E.C.; Funderburgh, M.L.; Birk, D.E.; Pearlman, E.; Guo, N.; Kao, W.W.-Y.; Funderburgh, J.L. Stem Cell Therapy Restores Transparency to Defective Murine Corneas. Stem Cells 2009, 27, 1635–1642. Available online: https://academic.oup.com/stmcls/article/27/7/1635/6402401 (accessed on 12 February 2023). [CrossRef][Green Version]
  55. Wang, Y.; Gao, G.; Wu, Y.; Wang, Y.; Wu, X.; Zhou, Q. S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/MTOR Signaling Pathway. Investig. Ophthalmol. Vis. Sci. 2020, 61, 19. [Google Scholar] [CrossRef] [PubMed]
  56. Li, Y.; Jin, R.; Li, L.; Choi, J.S.; Kim, J.; Yoon, H.J.; Park, J.H.; Yoon, K.C. Blue Light Induces Impaired Autophagy through Nucleotide-Binding Oligomerization Domain 2 Activation on the Mouse Ocular Surface. Int. J. Mol. Sci. 2021, 22, 2015. [Google Scholar] [CrossRef] [PubMed]
  57. Tang, Q.; Lu, B.; He, J.; Chen, X.; Fu, Q.; Han, H.; Luo, C.; Yin, H.; Qin, Z.; Lyu, D.; et al. Exosomes-Loaded Thermosensitive Hydrogels for Corneal Epithelium and Stroma Regeneration. Biomaterials 2022, 280, 121320. [Google Scholar] [CrossRef] [PubMed]
  58. Sun, X.; Song, W.; Teng, L.; Huang, Y.; Liu, J.; Peng, Y.; Lu, X.; Yuan, J.; Zhao, X.; Zhao, Q.; et al. MiRNA 24-3p-Rich Exosomes Functionalized DEGMA-Modified Hyaluronic Acid Hydrogels for Corneal Epithelial Healing. Biocative Mater. 2023, 25, 640–656. Available online: https://www.sciencedirect.com/science/article/pii/S2452199X22003097?via%3Dihub (accessed on 12 February 2023). [CrossRef]
  59. Lin, H.; Yiu, S.C. Dry Eye Disease: A Review of Diagnostic Approaches and Treatments. Saudi J. Ophthalmol. Off. J. Saudi Ophthalmol. Soc. 2014, 28, 173–181. [Google Scholar] [CrossRef][Green Version]
  60. Wu, K.Y.; Chen, W.T.; Chu-Bédard, Y.-K.; Patel, G.; Tran, S.D. Management of Sjogren’s Dry Eye Disease—Advances in Ocular Drug Delivery Offering a New Hope. Pharmaceutics 2023, 15, 147. [Google Scholar] [CrossRef]
  61. Lai, P.; Chen, X.; Guo, L.; Wang, Y.; Liu, X.; Liu, Y.; Zhou, T.; Huang, T.; Geng, S.; Luo, C.; et al. A Potent Immunomodulatory Role of Exosomes Derived from Mesenchymal Stromal Cells in Preventing CGVHD. J. Hematol. Oncol. 2018, 11, 135. [Google Scholar] [CrossRef][Green Version]
  62. Zhang, B.; Yeo, R.W.Y.; Lai, R.C.; Sim, E.W.K.; Chin, K.C.; Lim, S.K. Mesenchymal Stromal Cell Exosome–Enhanced Regulatory T-Cell Production through an Antigen-Presenting Cell–Mediated Pathway. Cytotherapy 2018, 20, 687–696. [Google Scholar] [CrossRef] [PubMed]
  63. Guo, R.; Liang, Q.; He, Y.; Wang, C.; Jiang, J.; Chen, T.; Zhang, D.; Hu, K. Mesenchymal Stromal Cells-Derived Extracellular Vesicles Regulate Dendritic Cell Functions in Dry Eye Disease. Cells 2023, 12, 33. [Google Scholar] [CrossRef] [PubMed]
  64. Wang, G.; Li, H.; Long, H.; Gong, X.; Hu, S.; Gong, C. Exosomes Derived from Mouse Adipose-Derived Mesenchymal Stem Cells Alleviate Benzalkonium Chloride-Induced Mouse Dry Eye Model via Inhibiting NLRP3 Inflammasome. Ophthalmic Res. 2022, 65, 40–51. [Google Scholar] [CrossRef] [PubMed]
  65. Yu, C.; Chen, P.; Xu, J.; Liu, Y.; Li, H.; Wang, L.; Di, G. HADSCs Derived Extracellular Vesicles Inhibit NLRP3 inflammasome Activation and Dry Eye. Sci. Rep. 2020, 10, 14521. [Google Scholar] [CrossRef]
  66. Ma, F.; Feng, J.; Liu, X.; Tian, Y.; Wang, W.-J.; Luan, F.-X.; Wang, Y.-J.; Yang, W.-Q.; Bai, J.-Y.; Zhang, Y.-Q.; et al. Ascorbic Acid-Coupled Mesenchymal Stem Cell-Derived Exosomes Ameliorate Dry Eye Disease. Preprints 2020, 2020060316. [Google Scholar] [CrossRef]
  67. Study Record|Beta ClinicalTrials.Gov. Available online: https://beta.clinicaltrials.gov/study/NCT04213248?tab=results (accessed on 13 February 2023).
  68. Zhao, J.; An, Q.; Zhu, X.; Yang, B.; Gao, X.; Niu, Y.; Zhang, L.; Xu, K.; Ma, D. Research Status and Future Prospects of Extracellular Vesicles in Primary Sjögren’s Syndrome. Stem Cell Res. Ther. 2022, 13, 230. [Google Scholar] [CrossRef]
  69. Gong, B.; Zheng, L.; Lu, Z.; Huang, J.; Pu, J.; Pan, S.; Zhang, M.; Liu, J.; Tang, J. Mesenchymal Stem Cells Negatively Regulate CD4+ T Cell Activation in Patients with Primary Sjögren Syndrome through the MiRNA-125b and MiRNA-155 TCR Pathway. Mol. Med. Rep. 2020, 23, 43. [Google Scholar] [CrossRef]
  70. Li, B.; Xing, Y.; Gan, Y.; He, J.; Hua, H. Labial Gland-Derived Mesenchymal Stem Cells and Their Exosomes Ameliorate Murine Sjögren’s Syndrome by Modulating the Balance of Treg and Th17 Cells. Stem Cell Res. Ther. 2021, 12, 478. Available online: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02541-0 (accessed on 13 February 2023). [CrossRef]
  71. Lind, E.F.; Ohashi, P.S. Mir-155, a Central Modulator of T-Cell Responses: Highlights. Eur. J. Immunol. 2014, 44, 11–15. [Google Scholar] [CrossRef]
  72. Rui, K.; Hong, Y.; Zhu, Q.; Shi, X.; Xiao, F.; Fu, H.; Yin, Q.; Xing, Y.; Wu, X.; Kong, X.; et al. Olfactory Ecto-Mesenchymal Stem Cell-Derived Exosomes Ameliorate Murine Sjögren’s Syndrome by Modulating the Function of Myeloid-Derived Suppressor Cells. Cell. Mol. Immunol. 2021, 18, 440–451. [Google Scholar] [CrossRef]
  73. Tomatsu, S.; Pitz, S.; Hampel, U. Ophthalmological Findings in Mucopolysaccharidoses. J. Clin. Med. 2019, 8, 1467. [Google Scholar] [CrossRef] [PubMed][Green Version]
  74. Coulson-Thomas, V.J.; Caterson, B.; Kao, W.W.-Y. Transplantation of Human Umbilical Mesenchymal Stem Cells Cures the Corneal Defects of Mucopolysaccharidosis VII Mice. Stem Cells 2013, 31, 2116–2126. Available online: https://academic.oup.com/stmcls/article/31/10/2116/6408126 (accessed on 13 February 2023). [CrossRef] [PubMed][Green Version]
  75. Flanagan, M.; Pathak, I.; Gan, Q.; Winter, L.; Emnet, R.; Akel, S.; Montaño, A.M. Umbilical Mesenchymal Stem Cell-Derived Extracellular Vesicles as Enzyme Delivery Vehicle to Treat Morquio a Fibroblasts. Stem Cell Res. Ther. 2021, 12, 276. [Google Scholar] [CrossRef] [PubMed]
  76. Doozandeh, A.; Yazdani, S. Neuroprotection in Glaucoma. J. Ophthalmic Vis. Res. 2016, 11, 209–220. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Mead, B.; Tomarev, S. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through MiRNA-Dependent Mechanisms. Stem Cells Transl. Med. 2017, 6, 1273–1285. [Google Scholar] [CrossRef] [PubMed]
  78. Mead, B.; Ahmed, Z.; Tomarev, S. Mesenchymal Stem Cell–Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. Investig. Opthalmol. Vis. Sci. 2018, 59, 5473. [Google Scholar] [CrossRef] [PubMed][Green Version]
  79. Mead, B.; Amaral, J.; Tomarev, S. Mesenchymal Stem Cell–Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Investig. Opthalmol. Vis. Sci. 2018, 59, 702. [Google Scholar] [CrossRef]
  80. Mead, B.; Chamling, X.; Zack, D.J.; Ahmed, Z.; Tomarev, S. TNFα-Mediated Priming of Mesenchymal Stem Cells Enhances Their Neuroprotective Effect on Retinal Ganglion Cells. Investig. Opthalmol. Vis. Sci. 2020, 61, 6. [Google Scholar] [CrossRef][Green Version]
  81. Park, M.; Shin, H.A.; Duong, V.-A.; Lee, H.; Lew, H. The Role of Extracellular Vesicles in Optic Nerve Injury: Neuroprotection and Mitochondrial Homeostasis. Cells 2022, 11, 3720. [Google Scholar] [CrossRef]
  82. Berry, M.; Ahmed, Z.; Morgan-Warren, P.; Fulton, D.; Logan, A. Prospects for MTOR-Mediated Functional Repair after Central Nervous System Trauma. Neurobiol. Dis. 2016, 85, 99–110. [Google Scholar] [CrossRef][Green Version]
  83. Park, K.K.; Liu, K.; Hu, Y.; Smith, P.D.; Wang, C.; Cai, B.; Xu, B.; Connolly, L.; Kramvis, I.; Sahin, M.; et al. Promoting Axon Regeneration in the Adult CNS by Modulation of the PTEN/MTOR Pathway. Science 2008, 322, 963–966. [Google Scholar] [CrossRef] [PubMed][Green Version]
  84. Katakowski, M.; Buller, B.; Zheng, X.; Lu, Y.; Rogers, T.; Osobamiro, O.; Shu, W.; Jiang, F.; Chopp, M. Exosomes from Marrow Stromal Cells Expressing MiR-146b Inhibit Glioma Growth. Cancer Lett. 2013, 335, 201–204. [Google Scholar] [CrossRef] [PubMed][Green Version]
  85. Douglas, M.R.; Morrison, K.C.; Jacques, S.J.; Leadbeater, W.E.; Gonzalez, A.M.; Berry, M.; Logan, A.; Ahmed, Z. Off-Target Effects of Epidermal Growth Factor Receptor Antagonists Mediate Retinal Ganglion Cell Disinhibited Axon Growth. Brain 2009, 132, 3102–3121. [Google Scholar] [CrossRef][Green Version]
  86. Koprivica, V.; Cho, K.-S.; Park, J.B.; Yiu, G.; Atwal, J.; Gore, B.; Kim, J.A.; Lin, E.; Tessier-Lavigne, M.; Chen, D.F.; et al. EGFR Activation Mediates Inhibition of Axon Regeneration by Myelin and Chondroitin Sulfate Proteoglycans. Science 2005, 310, 106–110. [Google Scholar] [CrossRef]
  87. Li, H.-J.; Pan, Y.-B.; Sun, Z.-L.; Sun, Y.-Y.; Yang, X.-T.; Feng, D.-F. Inhibition of MiR-21 Ameliorates Excessive Astrocyte Activation and Promotes Axon Regeneration Following Optic Nerve Crush. Neuropharmacology 2018, 137, 33–49. [Google Scholar] [CrossRef]
  88. Meng, F.; Henson, R.; Wehbe–Janek, H.; Ghoshal, K.; Jacob, S.T.; Patel, T. MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology 2007, 133, 647–658. [Google Scholar] [CrossRef] [PubMed][Green Version]
  89. Kwon, Y.H.; Fingert, J.H.; Kuehn, M.H.; Alward, W.L.M. Primary Open-Angle Glaucoma. N. Engl. J. Med. 2009, 360, 1113–1124. Available online: https://www.nejm.org/doi/full/10.1056/NEJMra0804630 (accessed on 13 February 2023). [CrossRef] [PubMed][Green Version]
  90. Tabak, S.; Schreiber-Avissar, S.; Beit-Yannai, E. Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma. Int. J. Mol. Sci. 2021, 22, 2421. [Google Scholar] [CrossRef]
  91. Li, Y.; Zheng, J.; Wang, X.; Wang, X.; Liu, W.; Gao, J. Mesenchymal Stem Cell-Derived Exosomes Protect Trabecular Meshwork from Oxidative Stress. Sci. Rep. 2021, 11, 14863. [Google Scholar] [CrossRef]
  92. Bradley, J.; Vranka, J.; Colvis, C.; Conger, D.; Alexander, J.; Fisk, A.; Samples, J.; Acott, T. Effect of Matrix Metalloproteinases Activity on Outflow in Perfused Human Organ Culture. Investig. Ophthalmol. Vis. Sci. 1999, 39, 2649–2658. [Google Scholar]
  93. Tamkovich, S.; Grigor’eva, A.; Eremina, A.; Tupikin, A.; Kabilov, M.; Chernykh, V.; Vlassov, V.; Ryabchikova, E. What Information Can Be Obtained from the Tears of a Patient with Primary Open Angle Glaucoma? Clin. Chim. Acta 2019, 495, 529–537. [Google Scholar] [CrossRef] [PubMed]
  94. Pantalon, A.; Obadă, O.; Constantinescu, D.; Feraru, C.; Chiseliţă, D. Inflammatory Model in Patients with Primary Open Angle Glaucoma and Diabetes. Int. J. Ophthalmol. 2019, 12, 795–801. [Google Scholar] [CrossRef] [PubMed]
  95. Li, J.; Zhou, Y.; Long, Q. Effects of Mesenchymal Stem Cells Derived Exosomes on Ultrastructure of Corneal Epithelium and Function of the Tear Film in Dry Eye BALB/c Mice. Investing. Opthalmol. Vis. Sci. 2019, 60, 4187. Available online: https://iovs.arvojournals.org/article.aspx?articleid=2743824 (accessed on 13 February 2023).
  96. Cuenca, N.; Fernández-Sánchez, L.; Campello, L.; Maneu, V.; De la Villa, P.; Lax, P.; Pinilla, I. Cellular Responses Following Retinal Injuries and Therapeutic Approaches for Neurodegenerative Diseases. Prog. Retin. Eye Res. 2014, 43, 17–75. [Google Scholar] [CrossRef] [PubMed]
  97. Deng, C.-L.; Hu, C.-B.; Ling, S.-T.; Zhao, N.; Bao, L.-H.; Zhou, F.; Xiong, Y.-C.; Chen, T.; Sui, B.-D.; Yu, X.-R.; et al. Photoreceptor Protection by Mesenchymal Stem Cell Transplantation Identifies Exosomal MiR-21 as a Therapeutic for Retinal Degeneration. Cell Death Differ. 2021, 28, 1041–1061. [Google Scholar] [CrossRef]
  98. Zhang, J.; Li, P.; Zhao, G.; He, S.; Xu, D.; Jiang, W.; Peng, Q.; Li, Z.; Xie, Z.; Zhang, H.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Retina in a Mouse Model of Retinitis Pigmentosa by Anti-Inflammation through MiR-146a-Nr4a3 Axis. Stem Cell Res. Ther. 2022, 13, 394. [Google Scholar] [CrossRef]
  99. Safwat, A.; Sabry, D.; Ragiae, A.; Amer, E.; Mahmoud, R.H.; Shamardan, R.M. Adipose mesenchymal stem cells–derived exosomes attenuate retina degeneration of streptozotocin-induced diabetes in rabbits. J. Circ. Biomark. 2018, 7, 1849454418807827. [Google Scholar] [CrossRef] [PubMed][Green Version]
  100. Li, W.; Jin, L.; Cui, Y.; Nie, A.; Xie, N.; Liang, G. Bone Marrow Mesenchymal Stem Cells-Induced Exosomal MicroRNA-486-3p Protects against Diabetic Retinopathy through TLR4/NF-ΚB Axis Repression. J. Endocrinol. Investig. 2021, 44, 1193–1207. [Google Scholar] [CrossRef]
  101. Li, W.; Jin, L.; Cui, Y.; Xie, N. Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomal MicroRNA-17-3p Ameliorates Inflammatory Reaction and Antioxidant Injury of Mice with Diabetic Retinopathy via Targeting STAT1. Int. Immunopharmacol. 2021, 90, 107010. [Google Scholar] [CrossRef]
  102. Gu, C.; Zhang, H.; Zhao, S.; He, D.; Gao, Y. Mesenchymal Stem Cell Exosomal MiR-146a Mediates the Regulation of the TLR4/MyD88/NF-ΚB Signaling Pathway in Inflammation Due to Diabetic Retinopathy. Comput. Math. Methods Med. 2022, 2022, 3864863. [Google Scholar] [CrossRef]
  103. Ebrahim, N.; El-Halim, H.E.A.; Helal, O.K.; El-Azab, N.E.-E.; Badr, O.A.M.; Hassouna, A.; Saihati, H.A.A.; Aborayah, N.H.; Emam, H.T.; El-wakeel, H.S.; et al. Effect of Bone Marrow Mesenchymal Stem Cells-Derived Exosomes on Diabetes-Induced Retinal Injury: Implication of Wnt/b-Catenin Signaling Pathway. Biomed. Pharmacother. 2022, 154, 113554. [Google Scholar] [CrossRef] [PubMed]
  104. Cao, X.; Xue, L.-D.; Di, Y.; Li, T.; Tian, Y.-J.; Song, Y. MSC-Derived Exosomal LncRNA SNHG7 Suppresses Endothelial-Mesenchymal Transition and Tube Formation in Diabetic Retinopathy via MiR-34a-5p/XBP1 Axis. Life Sci. 2021, 272, 119232. [Google Scholar] [CrossRef] [PubMed]
  105. Hajrasouliha, A.R.; Jiang, G.; Lu, Q.; Lu, H.; Kaplan, H.J.; Zhang, H.-G.; Shao, H. Exosomes from Retinal Astrocytes Contain Antiangiogenic Components That Inhibit Laser-Induced Choroidal Neovascularization. J. Biol. Chem. 2013, 288, 28058–28067. [Google Scholar] [CrossRef] [PubMed][Green Version]
  106. He, G.-H.; Zhang, W.; Ma, Y.-X.; Yang, J.; Chen, L.; Song, J.; Chen, S. Mesenchymal Stem Cells-Derived Exosomes Ameliorate Blue Light Stimulation in Retinal Pigment Epithelium Cells and Retinal Laser Injury by VEGF-Dependent Mechanism. Int. J. Ophthalmol. 2018, 11, 559–566. [Google Scholar] [CrossRef]
  107. Mathew, B.; Ravindran, S.; Liu, X.; Torres, L.; Chennakesavalu, M.; Huang, C.-C.; Feng, L.; Zelka, R.; Lopez, J.; Sharma, M.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles and Retinal Ischemia-Reperfusion. Biomaterials 2019, 197, 146–160. [Google Scholar] [CrossRef] [PubMed]
  108. Yu, Z.; Wen, Y.; Jiang, N.; Li, Z.; Guan, J.; Zhang, Y.; Deng, C.; Zhao, L.; Zheng, S.G.; Zhu, Y.; et al. TNF-α Stimulation Enhances the Neuroprotective Effects of Gingival MSCs Derived Exosomes in Retinal Ischemia-Reperfusion Injury via the MEG3/MiR-21a-5p Axis. Biomaterials 2022, 284, 121484. [Google Scholar] [CrossRef]
  109. Ma, M.; Li, B.; Zhang, M.; Zhou, L.; Yang, F.; Ma, F.; Shao, H.; Li, Q.; Li, X.; Zhang, X. Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes on Retinal Detachment. Exp. Eye Res. 2020, 191, 107899. [Google Scholar] [CrossRef]
  110. Dervenis, N.; Dervenis, P.; Sandinha, T.; Murphy, D.C.; Steel, D.H. Intraocular Tamponade Choice with Vitrectomy and Internal Limiting Membrane Peeling for Idiopathic Macular Hole: A Systematic Review and Meta-Analysis. Ophthalmol. Retina 2022, 6, 457–468. [Google Scholar] [CrossRef]
  111. Muqit, M.M.K.; Hamilton, R.; Ho, J.; Tucker, S.; Buck, H. Intravitreal Ocriplasmin for the Treatment of Vitreomacular Traction and Macular Hole- A Study of Efficacy and Safety Based on NICE Guidance. PLoS ONE 2018, 13, e0197072. [Google Scholar] [CrossRef][Green Version]
  112. Zhang, X.; Liu, J.; Yu, B.; Ma, F.; Ren, X.; Li, X. Effects of Mesenchymal Stem Cells and Their Exosomes on the Healing of Large and Refractory Macular Holes. Graefes Arch. Clin. Exp. Ophthalmol. 2018, 256, 2041–2052. [Google Scholar] [CrossRef]
  113. Valdes, L.M.; Sobrin, L. Uveitis Therapy: The Corticosteroid Options. Drugs 2020, 80, 765–773. [Google Scholar] [CrossRef] [PubMed]
  114. Duplechain, A.; Conrady, C.D.; Patel, B.C.; Baker, S. Uveitis. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. [Google Scholar]
  115. Shigemoto-Kuroda, T.; Oh, J.Y.; Kim, D.; Jeong, H.J.; Park, S.Y.; Lee, H.J.; Park, J.W.; Kim, T.W.; An, S.Y.; Prockop, D.J.; et al. MSC-Derived Extracellular Vesicles Attenuate Immune Responses in Two Autoimmune Murine Models: Type 1 Diabetes and Uveoretinitis. Stem Cell Rep. 2017, 8, 1214–1225. [Google Scholar] [CrossRef] [PubMed][Green Version]
  116. Bai, L.; Shao, H.; Wang, H.; Zhang, Z.; Su, C.; Dong, L.; Yu, B.; Chen, X.; Li, X.; Zhang, X. Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis. Sci. Rep. 2017, 7, 4323. [Google Scholar] [CrossRef][Green Version]
  117. Xie, R.; Bai, L.; Yang, J.; Li, Y.; Dong, L.; Ma, F.; Li, X.; Zhang, X. Effects of rat mesenchymal stem cell-derived exosomes on rat experimental autoimmune uveitis. Chin. J. Ocul. Fundus Dis. 2018, 34, 562–567. [Google Scholar]
  118. Li, Y.; Ren, X.; Zhang, Z.; Duan, Y.; Li, H.; Chen, S.; Shao, H.; Li, X.; Zhang, X. Effect of Small Extracellular Vesicles Derived from IL-10-Overexpressing Mesenchymal Stem Cells on Experimental Autoimmune Uveitis. Stem Cell Res. Ther. 2022, 13, 100. [Google Scholar] [CrossRef]
  119. Liu, Y.; Zhou, T.; Yang, Z.; Sun, X.; Huang, Z.; Deng, X.; He, C.; Liu, X. Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Attenuate Neuroinflammation and Promote Survival of Photoreceptor in Retinitis Pigmentosa. Investig. Ophthalmol. Vis. Sci. 2019, 60, 3108. [Google Scholar]
  120. Li, D.; Zhang, J.; Liu, Z.; Gong, Y.; Zheng, Z. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomal MiR-27b Attenuates Subretinal Fibrosis via Suppressing Epithelial–Mesenchymal Transition by Targeting HOXC6. Stem Cell Res. Ther. 2021, 12, 24. [Google Scholar] [CrossRef] [PubMed]
  121. Oh, J.Y.; Kim, T.W.; Jeong, H.J.; Lee, H.J.; Ryu, J.S.; Wee, W.R.; Heo, J.W.; Kim, M.K. Intraperitoneal Infusion of Mesenchymal Stem/Stromal Cells Prevents Experimental Autoimmune Uveitis in Mice. Mediat. Inflamm. 2014, 2014, 624640. [Google Scholar] [CrossRef] [PubMed][Green Version]
  122. Li, H.; Zhang, Z.; Li, Y.; Su, L.; Duan, Y.; Zhang, H.; An, J.; Ni, T.; Li, X.; Zhang, X. Therapeutic Effect of Rapamycin-Loaded Small Extracellular Vesicles Derived from Mesenchymal Stem Cells on Experimental Autoimmune Uveitis. Front. Immunol. 2022, 13, 864956. [Google Scholar] [CrossRef]
  123. Wei, W.; Ao, Q.; Wang, X.; Cao, Y.; Liu, Y.; Zheng, S.G.; Tian, X. Mesenchymal Stem Cell–Derived Exosomes: A Promising Biological Tool in Nanomedicine. Front. Pharmacol. 2021, 11, 590470. [Google Scholar] [CrossRef]
  124. Hoang, D.M.; Pham, P.T.; Bach, T.Q.; Ngo, A.T.L.; Nguyen, Q.T.; Phan, T.T.K.; Nguyen, G.H.; Le, P.T.T.; Hoang, V.T.; Forsyth, N.R.; et al. Stem Cell-Based Therapy for Human Diseases. Signal Transduct. Target. Ther. 2022, 7, 272. [Google Scholar] [CrossRef] [PubMed]
  125. Kou, M.; Huang, L.; Yang, J.; Chiang, Z.; Chen, S.; Liu, J.; Guo, L.; Zhang, X.; Zhou, X.; Xu, X.; et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Immunomodulation and Regeneration: A next Generation Therapeutic Tool? Cell Death Dis. 2022, 13, 580. [Google Scholar] [CrossRef] [PubMed]
  126. Varderidou-Minasian, S.; Lorenowicz, M.J. Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles in Tissue Repair: Challenges and Opportunities. Theranostics 2020, 10, 5979–5997. [Google Scholar] [CrossRef] [PubMed]
  127. Chen, S.; Sun, F.; Qian, H.; Xu, W.; Jiang, J. Preconditioning and Engineering Strategies for Improving the Efficacy of Mesenchymal Stem Cell-Derived Exosomes in Cell-Free Therapy. Stem Cells Int. 2022, 2022, 1779346. [Google Scholar] [CrossRef]
  128. Qazi, T.H.; Mooney, D.J.; Duda, G.N.; Geissler, S. Biomaterials That Promote Cell-Cell Interactions Enhance the Paracrine Function of MSCs. Biomaterials 2017, 140, 103–114. [Google Scholar] [CrossRef]
  129. Su, N.; Gao, P.-L.; Wang, K.; Wang, J.-Y.; Zhong, Y.; Luo, Y. Fibrous Scaffolds Potentiate the Paracrine Function of Mesenchymal Stem Cells: A New Dimension in Cell-Material Interaction. Biomaterials 2017, 141, 74–85. [Google Scholar] [CrossRef]
  130. Samsonraj, R.M.; Rai, B.; Sathiyanathan, P.; Puan, K.J.; Rötzschke, O.; Hui, J.H.; Raghunath, M.; Stanton, L.W.; Nurcombe, V.; Cool, S.M. Establishing Criteria for Human Mesenchymal Stem Cell Potency. Stem Cells 2015, 33, 1878–1891. [Google Scholar] [CrossRef]
  131. Sathiyanathan, P.; Samsonraj, R.M.; Tan, C.L.L.; Ling, L.; Lezhava, A.; Nurcombe, V.; Stanton, L.W.; Cool, S.M. A Genomic Biomarker That Identifies Human Bone Marrow-Derived Mesenchymal Stem Cells with High Scalability. Stem Cells Dayt. Ohio 2020, 38, 1124–1136. [Google Scholar] [CrossRef]
  132. Boulestreau, J.; Maumus, M.; Rozier, P.; Jorgensen, C.; Noël, D. Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging. Front. Cell Dev. Biol. 2020, 8, 107. [Google Scholar] [CrossRef][Green Version]
  133. Li, Y.; Wu, Q.; Wang, Y.; Li, L.; Bu, H.; Bao, J. Senescence of Mesenchymal Stem Cells (Review). Int. J. Mol. Med. 2017, 39, 775–782. [Google Scholar] [CrossRef][Green Version]
  134. Kouroupis, D.; Churchman, S.M.; McGonagle, D.; Jones, E.A. The Assessment of CD146-Based Cell Sorting and Telomere Length Analysis for Establishing the Identity of Mesenchymal Stem Cells in Human Umbilical Cord. F1000Research 2014, 3, 126. [Google Scholar] [CrossRef] [PubMed]
  135. Laschober, G.T.; Brunauer, R.; Jamnig, A.; Fehrer, C.; Greiderer, B.; Lepperdinger, G. Leptin Receptor/CD295 Is Upregulated on Primary Human Mesenchymal Stem Cells of Advancing Biological Age and Distinctly Marks the Subpopulation of Dying Cells. Exp. Gerontol. 2009, 44, 57–62. [Google Scholar] [CrossRef] [PubMed]
  136. Jung, E.M.; Kwon, O.; Kwon, K.-S.; Cho, Y.S.; Rhee, S.K.; Min, J.-K.; Oh, D.-B. Evidences for Correlation between the Reduced VCAM-1 Expression and Hyaluronan Synthesis during Cellular Senescence of Human Mesenchymal Stem Cells. Biochem. Biophys. Res. Commun. 2011, 404, 463–469. [Google Scholar] [CrossRef]
  137. Simmons, P.J.; Torok-Storb, B. Identification of Stromal Cell Precursors in Human Bone Marrow by a Novel Monoclonal Antibody, STRO-1. Blood 1991, 78, 55–62. [Google Scholar] [CrossRef][Green Version]
  138. Yun, S.P.; Han, Y.-S.; Lee, J.H.; Kim, S.M.; Lee, S.H. Melatonin Rescues Mesenchymal Stem Cells from Senescence Induced by the Uremic Toxin p-Cresol via Inhibiting MTOR-Dependent Autophagy. Biomol. Ther. 2018, 26, 389–398. [Google Scholar] [CrossRef] [PubMed]
  139. Chaker, D.; Mouawad, C.; Azar, A.; Quilliot, D.; Achkar, I.; Fajloun, Z.; Makdissy, N. Inhibition of the RhoGTPase Cdc42 by ML141 Enhances Hepatocyte Differentiation from Human Adipose-Derived Mesenchymal Stem Cells via the Wnt5a/PI3K/MiR-122 Pathway: Impact of the Age of the Donor. Stem Cell Res. Ther. 2018, 9, 167. [Google Scholar] [CrossRef] [PubMed][Green Version]
  140. Siegel, G.; Kluba, T.; Hermanutz-Klein, U.; Bieback, K.; Northoff, H.; Schäfer, R. Phenotype, Donor Age and Gender Affect Function of Human Bone Marrow-Derived Mesenchymal Stromal Cells. BMC Med. 2013, 11, 146. [Google Scholar] [CrossRef][Green Version]
  141. Ulum, B.; Teker, H.T.; Sarikaya, A.; Balta, G.; Kuskonmaz, B.; Uckan-Cetinkaya, D.; Aerts-Kaya, F. Bone Marrow Mesenchymal Stem Cell Donors with a High Body Mass Index Display Elevated Endoplasmic Reticulum Stress and Are Functionally Impaired. J. Cell. Physiol. 2018, 233, 8429–8436. [Google Scholar] [CrossRef]
  142. Li, C.; Zhao, H.; Cheng, L.; Wang, B. Allogeneic vs. Autologous Mesenchymal Stem/Stromal Cells in Their Medication Practice. Cell Biosci. 2021, 11, 187. [Google Scholar] [CrossRef]
More
ScholarVision Creations