Treating the Retinal Diseases with Mesenchymal Stem Cells

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1		Xiaomin Zhang	--	2777	2023-01-06 10:16:16	\|
2	format correct	Catherine Yang	+ 2 word(s)	2779	2023-01-06 10:24:19	\| \|
3	format correct	Catherine Yang	-5 word(s)	2774	2023-01-09 07:38:50	\|

This entry is adapted from the peer-reviewed paper 10.3390/genes13101901

Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies.

mesenchymal stem cell retinal diseases cell therapy exosome

1. Implications of Mesenchymal Stem Cell Therapy in Retinal Degeneration

Stem cell therapy has opened a new era of tissue regeneration. MSCs may provide an alternative source for retinal regeneration. In addition to the established multipotential of MSCs to differentiate into osteoblasts, adipocytes, and chondrocytes, they were seen to differentiate into retinal cells in early studies. Bone-marrow-derived MSCs (BMSCs) and adipose-tissue-derived MSCs (AMSCs) are shown to express RPE and photoreceptor cell markers by exposure to conditioned medium in vitro ^[1]^[2]. Intravenous injection of MSCs into diabetic rats resulted in the targeted migration of the transplanted MSCs to the damaged retina and the expression of astrocytes and photoreceptor cell markers. However, from a dialectical point of view, ectopic expression of some photoreceptor markers does not signify that cells differentiate into photoreceptors and does not mean these cells are functional. Researchers tried to replace damaged retinal cells by directional differentiation of MSCs in order to reconstruct the retinal neural network and restore the activity of nerve conduction ^[3]^[4]. In animal models of retinal laser injury, almost all MSCs migrated and integrated into the layers of the retina by intravitreal MSC injection ^[5]^[6]. Recently, Ripolles-Garcia A et al. showed that human donor photoreceptor precursor cells were generated in vitro from hESCs and were integrated and differentiated into the canine retina. Notably, these generated photoreceptors have synaptic pedicle-like structures which could establish contact with second-order neurons. Thus, their findings set the stage for evaluating functional vision restoration following photoreceptor replacement in canine models of inherited retinal degeneration ^[7].

In contrast, intravitreal administration of MSCs remained in the vitreous cavity and did not differentiate into neural or perivascular-like cells while preventing retinal ganglion cell loss by triggering an effective cytoprotective microenvironment in the models of diabetic and experimental ocular hypertension ^[8]^[9]. However, undifferentiated MSCs are able to express many mature neuronal and glial markers, such as βIII-tubulin and GFAP, which make them more controversial for early discoveries ^[10]^[11]. Conversely, they might be overly simplistic and optimistic for the concept of direct cell replacement, since retinal degeneration diseases usually involve several layers and cell types of retina. Instead, administrated MSCs with paracrine trophic effects and some capable of direct engraftment might allow the stem cells to maximize their potential in retinal regeneration ^[12]^[13]^[14]^[15].

2. Immunosuppressive Effect of Mesenchymal Stem Cells in Uveitis

Chronic and recurrent uveitis involving the choroid and retina are usually treated by corticosteroids and immunosuppressants with many serious potential side effects, including myelosuppression, tumor formation, and liver and kidney damage. By targeting different parts of the immune system, MSCs are supposed to inhibit the autoimmune response, allograft rejection, and graft-versus-host disease ^[16]. Theoretically, MSCs are superior to corticosteroids and immunosuppressants in that they also possess neurotrophic and antimicrobial effects ^[17]^[18]^[19].

MSCs are currently being tested in preclinical studies for the treatment of experimental autoimmune uveitis (EAU) owing to their immunosuppressive properties ^[20]. Yang et al. reported four cases of refractory uveitis resistant to traditional systemic administration, which resolved after intravenous injection with human-umbilical-cord-derived MSCs (hUMSCs) ^[21]. A single course of MSC-based therapy at the onset of the disease suffices to protect against ocular inflammation in EAU ^[22]. Moreover, double treatments of MSCs with longer intervals have a significant curing effect ^[23]. The researchers' studies indicated that MSC-based therapy is more effective in controlling inflammation, reducing relapses, and protecting the retina in recurrent EAU than dexamethasone. The beneficial effects of MSCs in recurrent EAU were attributed to a significant decrease in Th1/Th17-mediated inflammation, to regulation of the balance between Th17 and Tregs, and to suppression of the function of antigen-presenting cells ^[19]^[23]. Further study demonstrated that the immunomodulatory function of MSCs might be mediated through the CD73/adenosine pathway in human and mouse T cells. CD73 on MSCs, upregulated by transforming growth factor-β1 (TGF-β1), cooperated with CD39 and CD73 on activated T cells to produce adenosine, resulting in inhibition of T-cell proliferation ^[24]. Injection of MSCs regulated STAT1 and STAT6 phosphorylation to reduce the levels of migration-related proteins in dendritic cells (DCs) and inhibit the proliferation of DCs ^[25]. Recent research shows that MSCs continue to play a vital role in EAU, as they inhibit the activation of CD4+T cells by direct intercellular contact and activation of prostaglandin signaling ^[26].

3. Neuroprotective Effect of Mesenchymal Stem Cells in Reducing or Delaying the Retinal Tissue Damage

MSCs are able to regulate the toll-like receptor 4 signaling pathway and pro-inflammatory factors such as tumor necrosis factor-α, interleukin (IL)-1β, and reactive oxygen species to reduce retinal cell apoptosis, increase retinal inner layer thickness, and reduce neuroinflammation ^[27]. Furthermore, plenty of studies have shown that MSCs are capable of secreting a variety of neurotrophic factors, such as basic fibroblast growth factors (bFGF), ciliary neurotrophic factors, ganglion-cell-derived neurotrophic factors (GDNF), nerve growth factors (NGF), and brain-derived neurotrophic factors in the treatment of retinal diseases ^[28]^[29]. Under the effect of neurotrophic factors secreted by MSCs, conditioned medium of MSCs can promote the photoreceptor cell proliferation in vitro and inhibit their death ^[30].

In the animal model of retinal degeneration, rats suffering from retinitis pigmentosa were given subretinal injection or intravenous injection with MSCs, which successfully inhibits retinal degeneration progress and protects the function of the retina, but transplanted MSCs did not migrate or integrate into the retina ^[4]^[31]^[32]. As for animal models of retinal ischemia reperfusion injury and glaucoma, intravitreal injection of MSCs could significantly improve the retinal ganglion cell survival ^[9]^[33]^[34]^[35]. MSCs distributed along the inner limiting membrane expressed a variety of neurotrophic factors, but only a handful of stem cells could migrate into the retina. Coculture of MSCs with retinal explants also confirmed the reduction in apoptosis and increase in the nerve fiber layer and inner plexiform layer thicknesses. Cell secretome demonstrated that MSCs secrete a number of neuroprotective proteins and suggest that platelet-derived growth factor secretion in particular may play an important role in MSC-mediated retinal ganglion cell neuroprotection ^[36]. MSCs might display their therapeutic effect in a paracrine fashion by secreting neuroprotective and anti-inflammatory factors to preserve the homeostasis of the ECM and regulate the intraocular microenvironment, which is beneficial for the integrity of the retina and tissue repair ^[37]. This experimental evidence all points to the speculation that the paracrine effect of MSCs may play a key role in the method of cell protection on the retina instead of migrating into the retina or differentiating into retina cells. In these diseases, MSCs give a neurotrophic effect, mainly by secreting neurotrophic factors, in addition to other possible mechanisms of MSCs, which include regulating the inflammatory process, repairing the blood vessel damage, and promoting synaptic regeneration by adjusting the inhibiting signal to activate the intrinsic repair mechanisms.

4. Tissue Repair and Inflammatory Chemotaxis of Mesenchymal Stem Cells

Pathological process of inflammatory reaction and tissue damage are involved in the above diseases such as uveitis, laser-induced retinal damage, ischemia injury, and diabetic retinopathy. MSCs play a role in anti-inflammation and promoting restoration of the retinal tissue damage. MSCs have the capacity to home into damaged tissue with inflammation, probably in response to chemokines, adhesion molecules, and matrix metalloproteinases, following intravenous injection ^[5]^[38]. However, the specific mechanism still remains a mystery ^[39]. In vitro results suggested that the stromal-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) and hepatocyte growth factor/c-met (HGF/c-met) axes, along with MMPs, act as important signals for migration and homing of mesenchymal stem cells ^[40]^[41]^[42]^[43]. An in vivo study also demonstrated that src family protein kinases are activated by SDF-1/CXCR4 signaling and play an essential role in SDF-1/CXCR4-mediated MSCs’ chemotactic response and ischemic cardiac recruitment ^[44].

5. Antioxidative Properties of Mesenchymal Stem Cells

ROS levels increase dramatically under environmental stress, which causes serious damage to cellular structures in retinal disease. As hMSCs were able to scavenge free radicals, promote endogenous antioxidant defenses, alter mitochondrial bioenergetics, transfer mitochondria to impaired cells, and effectively regulate oxidative stress, they have been studied as a treatment for oxidative injury. Ohkouchi et al. showed that MSCs elevated the survival rate of A549 cells through Stanniocalcin 1 upregulation ^[45]. Injection of AMSCs into the subretinal space of mice under oxidative stress protected and rescued RPE and photosensor cells ^[46].

6. Angiogenic Potentials of Mesenchymal Stem Cells

Abnormal angiogenesis is one of the main reasons for many ocular diseases, including DR, retinopathy of prematurity, and AMD. As MSCs can secrete angiogenesis-related factors and proteins, such as VEGF, fibroblast growth factor, HGF, TGF-β1, and insulin-like growth factor 1, they can promote angiogenesis and repair retinal ischemic injury ^[47]^[48]^[49].

Studies have shown that adult stem cells ^[50], AMSCs ^[51], iPSCs ^[52], and autologous BMSCs ^[53] are promising treatment options for animal models of DR and its complications. Elevated blood glucose levels in patients with DR lead to increased levels of reactive oxygen species (ROS), damaged pericytes and endothelial cells, vascular degeneration, and formation of new vessels. MSCs can not only differentiate into pericytes and reverse the changes in extracellular matrix proteins ^[54], but also inhibit the inflammatory response caused by oxidative stress through reducing the levels of pro-inflammatory factors, calcium, and ROS ^[55]. At the same time, the expression of intraocular nerve growth factor, bFGF, GDNF, and other nutritional factors, such as NGF and NT-3, can be induced to reduce nerve cell apoptosis ^[56].

In addition, MSCs also have anti-angiogenic effects in proliferative retinopathy. High levels of TGF-β1 secreted from human placental amniotic membrane derived MSCs demonstrated rescue potential on suppressing retinal neovascularization in a mouse model of oxygen-induced retinopathy ^[48].

7. Mitochondria Donation

Mitochondria create chemical energy for biochemical activities. A majority of mitochondrial proteins are encoded from nucleus DNA, maintaining mitochondrial functions, while mitochondria also contains its own DNA, known as mitochondrial DNA, which encodes 13 proteins ^[57]. Dysfunction of mitochondria is a signal indicating cellular senescence, and mitochondrial injury finally results in RPE cell death and degenerative retinal disease ^[58]. Both aging and hyperglycemia can lead to oxidative stress, damaging mitochondria and accelerating AMD and RD development ^[59]. In glaucoma, mitochondrial dysfunction is accompanied with retinal ganglion cell (RGC) degeneration ^[60], which is difficult to repair.

A fascinating and creative way that MSCs rescue impaired neural cells has provoked profound thought. Through different approaches, MSCs can deliver their own mitochondria to injured cells, in order to promote their repair and regeneration. This phenomenon was first described by Spees et al., who cocultured mitochondrial gene-depleted cells with MSCs. The mutant cells with enhanced mitochondria showed expression of mitochondrial proteins, and significantly increased ATP production and decreased lactate levels, a byproduct of anerobic respiration ^[61]. Previous studies have revealed several ways that mitochondria can be transferred, such as via tunneling nanotubes, gap junctions, or exosomes ^[62]. This kind of donation pathway is proven in ocular cells, including the corneal endothelium, RPE, and photoreceptors ^[63]. Intravitreal iPSC-derived MSC transplantation can significantly transfer mitochondria to damaged RGCs and improve retinal function ^[64].

8. Restraint of Cell Migration—Retinal Barriers

The adult visual pathway can possibly rebuild new synaptic interactions and guide new axons in certain circumstances, which provide an opportunity for cellular therapy. However, being similar to the central nervous system, the retina is not easily influenced by the outside factors, for example, stem cells, due to the retinal barriers. The blood–retinal barrier is part of the blood–ocular barrier that consists of retinal vascular endothelium and RPE ^[65]. The physiological barrier of retinal blood vessels comprises a single layer of non-fenestrated endothelial cells which maintain the inner blood–retinal barrier. The tight junctions between retinal epithelial cells, which form the outer blood–retinal barrier, prevent the passage of large molecules from choriocapillaris into the retina. In addition, internal and external limiting membrane, extracellular matrix components (such as chondroitin sulfate proteoglycans), active RGC synapses, glial scars produced by reactive gliosis in the injury, and pathological conditions are also important parts of the retina barriers ^[66].

Whether using local or systemic administration, MSCs were not seen to have migrated or integrated into the retina on an ideal scale while the retinal barriers were relatively integrated ^[4]^[33]^[34]. Thus, these retinal barriers remain the major obstacle for directional differentiation of stem cells to replace damaged retinal cells. A previous study delineated that retinal MSCs’ migration correlated positively with the amount of peeled internal limiting membrane, and targeted disruption of glial reactivity, with α-aminoadipic acid treatment, dramatically improved the structural integration of intravitreally transplanted cells ^[67]. By the manipulation of mechanical injury, incorporation of grafted stem cells was seen in 50% of the injured retinas, as well as subsequent differentiation into the neuronal and glial lineage, and formation of synapse-like structures were implied in the adult rat retina ^[68]. Another study showed that matrix metalloproteinase-2 can promote host–donor integration by degrading CD44 and neurocan at the outer surface of the degenerative retina without disruption of the host retinal architecture ^[69]. In addition, subretinal injection with chondroitinase ABC combined with enhanced immune suppression caused a dramatic increase in the migration of stem cells into all the retinal cell layers ^[66].

MSCs also have limitations for human retinal disease treatment due to the vulnerability of their expression. Some new technologies, such as gene therapy, retinal organoids in vitro, and bio-printing technology, have demonstrated prospective therapeutic capabilities to repair damaged retinal cells.

Erythropoietin-engineered human MSCs enhance differentiation into retinal photoreceptors in retinal degenerative diseases ^[70]. HiPSC-derived RGCs are seeded on a biodegradable poly (lactic-co-glycolic acid) scaffold to create an engineered biomaterial ^[71]. Retinal-ganglion-like cells differentiated from dental pulp stem cells using 3D networks to replace the lost and damaged RGCs ^[72].

9. New Insights about Exosomes Derived from Mesenchymal Stem Cells

Exosomes are the tiniest extracellular vesicles with bi-lipid membranes shuttling active cargoes (for example genetic material, proteins, and other biologically active molecules) involved in the complex intercellular communication system ^[73]. Being released by various cell types (such as B and T cells, DCs, cancer cells, stem cells, and endothelial cells), the main traits of exosomes are in accordance with the function of their original cells.

Recent discoveries noticed that MSC-derived exosomes, 50–150 nm microvesicles, could inherit the multiple functions from MSCs and might be the key mediators of MSC paracrine activity ^[74]^[75]. They have been studied in various disease models with many encouraging results. In cardiovascular disease, the infarct size and cardiac function were ameliorated in myocardial ischemia/reperfusion injury and acute myocardial infarction following administration of exosomes derived from MSCs ^[76]. MSC-derived exosomes also play a role in inflammation regulation and ischemia/reperfusion-induced renal injury repair, partially by suppressing the recruitment and activation of macrophages related to the C-C motif chemokine receptor-2 expression ^[77]. Extracellular vesicles exhibit immunomodulatory properties similar to their original MSCs through inhibitory activity on B-cell proliferation, intervention of shifting T cells from an activated status to a T regulatory phenotype, reduction in interferon-γ production, and increased release of immunosuppressive cytokines (such as prostaglandin E2, TGF-β, IL-10, and IL-6) ^[78]^[79]^[80]^[81]. In addition, the protective effect of MSCs on acute lung injury can be potentiated by ischemic preconditioning through the secretion of exosomes ^[82]. In neurological diseases, a recent study demonstrated that systemic administration of cell-free exosomes generated by MSCs improves functional recovery in rats that suffered from traumatic brain injury, while another group proposed that combined MSCs and MSC-derived exosome therapy displayed the best result in reducing the brain infarct volume and preserving neurological function in rats after acute ischemic stroke ^[83]^[84].

Although preclinical studies of exosomes derived from stem cells have been applied to the treatment for a variety of diseases, very few results came out in ophthalmology. The researchers first observed the therapeutic effect of exosomes derived from MSCs in retinal dysfunction ^[85]. MSC-derived exosomes were able to pass retinal barriers and diffuse throughout the retina after intravitreal injection. After laser injury, MSC/exosome-treated groups showed smaller lesioned areas, less TUNEL-positive cells, and better ERG responses. Further in vivo and in vitro experiments suggested that their suppression of injury-induced inflammation may be via the down-regulation of monocyte chemotactic protein-1.

While extant obstacles limit the clinical applications of simple stem cell treatment for retinal diseases, such as retinal barriers, the alternative application of MSC-derived exosomes remains more promising, primarily due to their inherited abilities, low immunogenicity, long half-life in circulation, and other cell-free advantages. Additionally, MSCs can produce a higher number of exosomes compared to other cells. However, whether MSC-derived exosomes preserve the same effective properties compared to the cells themselves remains controversial, as MSCs may act by releasing other active soluble factors and the biological features of exosomes may vary with different extracellular environments. Therefore, further studies are required to understand the full dimension of this complex intercellular communication system and how it can be optimized to take full advantage of its therapeutic effects.

References

Tao, Y.X.; Xu, H.W.; Zheng, Q.Y.; FitzGibbon, T. Noggin induces human bone marrow-derived mesenchymal stem cells to differentiate into neural and photoreceptor cells. Indian J. Exp. Biol. 2010, 48, 444–452.
Vossmerbaeumer, U.; Ohnesorge, S.; Kuehl, S.; Haapalahti, M.; Kluter, H.; Jonas, J.B.; Thierse, H.J.; Bieback, K. Retinal pigment epithelial phenotype induced in human adipose tissue-derived mesenchymal stromal cells. Cytotherapy 2009, 11, 177–188.
Kicic, A.; Shen, W.Y.; Wilson, A.S.; Constable, I.J.; Robertson, T.; Rakoczy, P.E. Differentiation of marrow stromal cells into photoreceptors in the rat eye. J. Neurosci. 2003, 23, 7742–7749.
Wang, S.; Lu, B.; Girman, S.; Duan, J.; McFarland, T.; Zhang, Q.S.; Grompe, M.; Adamus, G.; Appukuttan, B.; Lund, R. Non-invasive stem cell therapy in a rat model for retinal degeneration and vascular pathology. PLoS ONE 2010, 5, e9200.
Hou, H.Y.; Liang, H.L.; Wang, Y.S.; Zhang, Z.X.; Wang, B.R.; Shi, Y.Y.; Dong, X.; Cai, Y. A therapeutic strategy for choroidal neovascularization based on recruitment of mesenchymal stem cells to the sites of lesions. Mol. Ther. 2010, 18, 1837–1845.
Castanheira, P.; Torquetti, L.; Nehemy, M.B.; Goes, A.M. Retinal incorporation and differentiation of mesenchymal stem cells intravitreally injected in the injured retina of rats. Arq. Bras. Oftalmol. 2008, 71, 644–650.
Ripolles-Garcia, A.; Dolgova, N.; Phillips, M.J.; Savina, S.; Ludwig, A.L.; Stuedemann, S.A.; Nlebedum, U.; Wolfe, J.H.; Garden, O.A.; Maminishkis, A.; et al. Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs. Stem. Cell. Rep. 2022, 17, 1824–1841.
Ezquer, M.; Urzua, C.A.; Montecino, S.; Leal, K.; Conget, P.; Ezquer, F. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem. Cell. Res. Ther. 2016, 7, 42.
Emre, E.; Yuksel, N.; Duruksu, G.; Pirhan, D.; Subasi, C.; Erman, G.; Karaoz, E. Neuroprotective effects of intravitreally transplanted adipose tissue and bone marrow-derived mesenchymal stem cells in an experimental ocular hypertension model. Cytotherapy 2015, 17, 543–559.
Karaoz, E.; Demircan, P.C.; Saglam, O.; Aksoy, A.; Kaymaz, F.; Duruksu, G. Human dental pulp stem cells demonstrate better neural and epithelial stem cell properties than bone marrow-derived mesenchymal stem cells. Histochem. Cell. Biol. 2011, 136, 455–473.
Tamaki, Y.; Nakahara, T.; Ishikawa, H.; Sato, S. In vitro analysis of mesenchymal stem cells derived from human teeth and bone marrow. Odontology 2013, 101, 121–132.
Zhang, Y.; Arner, K.; Ehinger, B.; Perez, M.T. Limitation of anatomical integration between subretinal transplants and the host retina. Investig. Ophthalmol. Vis. Sci. 2003, 44, 324–331.
Yellowlees Douglas, J.; Bhatwadekar, A.D.; Li Calzi, S.; Shaw, L.C.; Carnegie, D.; Caballero, S.; Li, Q.; Stitt, A.W.; Raizada, M.K.; Grant, M.B. Bone marrow-CNS connections: Implications in the pathogenesis of diabetic retinopathy. Prog. Retin. Eye Res. 2012, 31, 481–494.
Radtke, N.D.; Seiler, M.J.; Aramant, R.B.; Petry, H.M.; Pidwell, D.J. Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients. Am. J. Ophthalmol. 2002, 133, 544–550.
Marc, R.E.; Jones, B.W.; Watt, C.B.; Strettoi, E. Neural remodeling in retinal degeneration. Prog. Retin. Eye Res. 2003, 22, 607–655.
Duffy, M.M.; Ritter, T.; Ceredig, R.; Griffin, M.D. Mesenchymal stem cell effects on T-cell effector pathways. Stem. Cell. Res. Ther. 2011, 2, 34.
Maltman, D.J.; Hardy, S.A.; Przyborski, S.A. Role of mesenchymal stem cells in neurogenesis and nervous system repair. Neurochem. Int. 2011, 59, 347–356.
Meisel, R.; Brockers, S.; Heseler, K.; Degistirici, O.; Bulle, H.; Woite, C.; Stuhlsatz, S.; Schwippert, W.; Jager, M.; Sorg, R.; et al. Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 2011, 25, 648–654.
Skrahin, A.; Ahmed, R.K.; Ferrara, G.; Rane, L.; Poiret, T.; Isaikina, Y.; Skrahina, A.; Zumla, A.; Maeurer, M.J. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: An open-label phase 1 safety trial. Lancet Res. Med. 2014, 2, 108–122.
Gebler, A.; Zabel, O.; Seliger, B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol. Med. 2012, 18, 128–134.
Yang, J.; Ren, X.J.; Chen, X.T.; Jiang, Y.F.; Han, Z.B.; Han, Z.C.; Li, X.R.; Zhang, X.M. Human umbilical cord-derived mesenchymal stem cells treatment for refractory uveitis: A case series. Int. J. Ophthalmol. 2021, 14, 1784–1790.
Zhang, L.; Zheng, H.; Shao, H.; Nian, H.; Zhang, Y.; Bai, L.; Su, C.; Liu, X.; Dong, L.; Li, X.; et al. Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental autoimmune uveitis of rats. Investig. Ophthalmol. Vis. Sci. 2014, 55, 5561–5571.
Zhao, P.T.; Zhang, L.J.; Shao, H.; Bai, L.L.; Yu, B.; Su, C.; Dong, L.J.; Liu, X.; Li, X.R.; Zhang, X.M. Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis. Int. J. Ophthalmol. 2016, 9, 1381–1389.
Chen, X.; Shao, H.; Zhi, Y.; Xiao, Q.; Su, C.; Dong, L.; Liu, X.; Li, X.; Zhang, X. CD73 Pathway Contributes to the Immunosuppressive Ability of Mesenchymal Stem Cells in Intraocular Autoimmune Responses. Stem. Cells Dev. 2016, 25, 337–346.
Dong, L.; Chen, X.; Shao, H.; Bai, L.; Li, X.; Zhang, X. Mesenchymal Stem Cells Inhibited Dendritic Cells Via the Regulation of STAT1 and STAT6 Phosphorylation in Experimental Autoimmune Uveitis. Curr. Mol. Med. 2018, 17, 478–487.
Saldinger, L.K.; Nelson, S.G.; Bellone, R.R.; Lassaline, M.; Mack, M.; Walker, N.J.; Borjesson, D.L. Horses with equine recurrent uveitis have an activated CD4+ T-cell phenotype that can be modulated by mesenchymal stem cells in vitro. Vet. Ophthalmol. 2020, 23, 160–170.
Ji, S.; Xiao, J.; Liu, J.; Tang, S. Human Umbilical Cord Mesenchymal Stem Cells Attenuate Ocular Hypertension-Induced Retinal Neuroinflammation via Toll-Like Receptor 4 Pathway. Stem. Cells Int. 2019, 2019, 9274585.
Ng, T.K.; Fortino, V.R.; Pelaez, D.; Cheung, H.S. Progress of mesenchymal stem cell therapy for neural and retinal diseases. World. J. Stem. Cells 2014, 6, 111–119.
Sun, J.; Mandai, M.; Kamao, H.; Hashiguchi, T.; Shikamura, M.; Kawamata, S.; Sugita, S.; Takahashi, M. Protective Effects of Human iPS-Derived Retinal Pigmented Epithelial Cells in Comparison with Human Mesenchymal Stromal Cells and Human Neural Stem Cells on the Degenerating Retina in rd1 mice. Stem. Cells 2015, 33, 1543–1553.
Zhang, J.; Shan, Q.; Ma, P.; Jiang, Y.; Chen, P.; Wen, J.; Zhou, Y.; Qian, H.; Pei, X. Differentiation potential of bone marrow mesenchymal stem cells into retina in normal and laser-injured rat eye. Sci. China C Life Sci. 2004, 47, 241–250.
Arnhold, S.; Heiduschka, P.; Klein, H.; Absenger, Y.; Basnaoglu, S.; Kreppel, F.; Henke-Fahle, S.; Kochanek, S.; Bartz-Schmidt, K.U.; Addicks, K.; et al. Adenovirally transduced bone marrow stromal cells differentiate into pigment epithelial cells and induce rescue effects in RCS rats. Investig. Ophthalmol. Vis. Sci. 2006, 47, 4121–4129.
Arnhold, S.; Absenger, Y.; Klein, H.; Addicks, K.; Schraermeyer, U. Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefes Arch. Clin. Exp. Ophthalmol. 2007, 245, 414–422.
Li, N.; Li, X.R.; Yuan, J.Q. Effects of bone-marrow mesenchymal stem cells transplanted into vitreous cavity of rat injured by ischemia/reperfusion. Graefes Arch. Clin. Exp. Ophthalmol. 2009, 247, 503–514.
Johnson, T.V.; Bull, N.D.; Hunt, D.P.; Marina, N.; Tomarev, S.I.; Martin, K.R. Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Investig. Ophthalmol. Vis. Sci. 2010, 51, 2051–2059.
Mead, B.; Hill, L.J.; Blanch, R.J.; Ward, K.; Logan, A.; Berry, M.; Leadbeater, W.; Scheven, B.A. Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma. Cytotherapy 2016, 18, 487–496.
Johnson, T.V.; DeKorver, N.W.; Levasseur, V.A.; Osborne, A.; Tassoni, A.; Lorber, B.; Heller, J.P.; Villasmil, R.; Bull, N.D.; Martin, K.R.; et al. Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome. Brain 2014, 137, 503–519.
Jiang, Y.; Zhang, Y.; Zhang, L.; Wang, M.; Zhang, X.; Li, X. Therapeutic effect of bone marrow mesenchymal stem cells on laser-induced retinal injury in mice. Int. J. Mol. Sci. 2014, 15, 9372–9385.
Motegi, S.I.; Ishikawa, O. Mesenchymal stem cells: The roles and functions in cutaneous wound healing and tumor growth. J. Dermatol. Sci. 2017, 86, 83–89.
Eseonu, O.I.; De Bari, C. Homing of mesenchymal stem cells: Mechanistic or stochastic? Implications for targeted delivery in arthritis. Rheumatology 2015, 54, 210–218.
Neuss, S.; Becher, E.; Woltje, M.; Tietze, L.; Jahnen-Dechent, W. Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem. Cells 2004, 22, 405–414.
Shi, M.; Li, J.; Liao, L.; Chen, B.; Li, B.; Chen, L.; Jia, H.; Zhao, R.C. Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: Role in homing efficiency in NOD/SCID mice. Haematologica 2007, 92, 897–904.
Son, B.R.; Marquez-Curtis, L.A.; Kucia, M.; Wysoczynski, M.; Turner, A.R.; Ratajczak, J.; Ratajczak, M.Z.; Janowska-Wieczorek, A. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem. Cells 2006, 24, 1254–1264.
De Becker, A.; Van Hummelen, P.; Bakkus, M.; Vande Broek, I.; De Wever, J.; De Waele, M.; Van Riet, I. Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica 2007, 92, 440–449.
Cheng, M.; Huang, K.; Zhou, J.; Yan, D.; Tang, Y.L.; Zhao, T.C.; Miller, R.J.; Kishore, R.; Losordo, D.W.; Qin, G. A critical role of Src family kinase in SDF-1/CXCR4-mediated bone-marrow progenitor cell recruitment to the ischemic heart. J. Mol. Cell. Cardiol. 2015, 81, 49–53.
Ohkouchi, S.; Block, G.J.; Katsha, A.M.; Kanehira, M.; Ebina, M.; Kikuchi, T.; Saijo, Y.; Nukiwa, T.; Prockop, D.J. Mesenchymal stromal cells protect cancer cells from ROS-induced apoptosis and enhance the Warburg effect by secreting STC1. Mol. Ther. 2012, 20, 417–423.
Barzelay, A.; Weisthal Algor, S.; Niztan, A.; Katz, S.; Benhamou, M.; Nakdimon, I.; Azmon, N.; Gozlan, S.; Mezad-Koursh, D.; Neudorfer, M.; et al. Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress. Stem. Cells Int. 2018, 2018, 9682856.
Psaltis, P.J.; Zannettino, A.C.; Worthley, S.G.; Gronthos, S. Concise review: Mesenchymal stromal cells: Potential for cardiovascular repair. Stem. Cells 2008, 26, 2201–2210.
Kim, K.S.; Park, J.M.; Kong, T.; Kim, C.; Bae, S.H.; Kim, H.W.; Moon, J. Retinal Angiogenesis Effects of TGF-beta1 and Paracrine Factors Secreted From Human Placental Stem Cells in Response to a Pathological Environment. Cell. Transplant. 2016, 25, 1145–1157.
Ribot, J.; Caliaperoumal, G.; Paquet, J.; Boisson-Vidal, C.; Petite, H.; Anagnostou, F. Type 2 diabetes alters mesenchymal stem cell secretome composition and angiogenic properties. J. Cell. Mol. Med. 2017, 21, 349–363.
Gaddam, S.; Periasamy, R.; Gangaraju, R. Adult Stem Cell Therapeutics in Diabetic Retinopathy. Int. J. Mol. Sci. 2019, 20, 4876.
Elshaer, S.L.; Evans, W.; Pentecost, M.; Lenin, R.; Periasamy, R.; Jha, K.A.; Alli, S.; Gentry, J.; Thomas, S.M.; Sohl, N.; et al. Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2(Akita) mouse. Stem. Cell. Res. Ther. 2018, 9, 322.
Yang, J.; Cai, B.; Glencer, P.; Li, Z.; Zhang, X.; Li, X. Induced Pluripotent Stem Cells and Outer Retinal Disease. Stem. Cells Int 2016, 2016, 2850873.
Gu, X.; Yu, X.; Zhao, C.; Duan, P.; Zhao, T.; Liu, Y.; Li, S.; Yang, Z.; Li, Y.; Qian, C.; et al. Efficacy and Safety of Autologous Bone Marrow Mesenchymal Stem Cell Transplantation in Patients with Diabetic Retinopathy. Cell. Physiol. Biochem. 2018, 49, 40–52.
Herrmann, M.; Bara, J.J.; Sprecher, C.M.; Menzel, U.; Jalowiec, J.M.; Osinga, R.; Scherberich, A.; Alini, M.; Verrier, S. Pericyte plasticity-comparative investigation of the angiogenic and multilineage potential of pericytes from different human tissues. Eur. Cell. Mater. 2016, 31, 236–249.
Oses, C.; Olivares, B.; Ezquer, M.; Acosta, C.; Bosch, P.; Donoso, M.; Leniz, P.; Ezquer, F. Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: Potential application in the treatment of diabetic neuropathy. PLoS ONE 2017, 12, e0178011.
Fiori, A.; Terlizzi, V.; Kremer, H.; Gebauer, J.; Hammes, H.P.; Harmsen, M.C.; Bieback, K. Mesenchymal stromal/stem cells as potential therapy in diabetic retinopathy. Immunobiology 2018, 223, 729–743.
Nunnari, J.; Suomalainen, A. Mitochondria: In sickness and in health. Cell 2012, 148, 1145–1159.
Kaarniranta, K.; Uusitalo, H.; Blasiak, J.; Felszeghy, S.; Kannan, R.; Kauppinen, A.; Salminen, A.; Sinha, D.; Ferrington, D. Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration. Prog. Retin. Eye Res. 2020, 79, 100858.
Tong, Y.; Zhang, Z.; Wang, S. Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration. Front. Aging 2022, 3, 926627.
Jassim, A.H.; Inman, D.M.; Mitchell, C.H. Crosstalk Between Dysfunctional Mitochondria and Inflammation in Glaucomatous Neurodegeneration. Front. Pharmacol. 2021, 12, 699623.
Mohammadalipour, A.; Dumbali, S.P.; Wenzel, P.L. Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy. Front. Cell. Dev. Biol. 2020, 8, 603292.
Herst, P.M.; Dawson, R.H.; Berridge, M.V. Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer. Front. Oncol. 2018, 8, 344.
Adak, S.; Magdalene, D.; Deshmukh, S.; Das, D.; Jaganathan, B.G. A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases. Stem. Cell. Rev. Rep. 2021, 17, 1154–1173.
Jiang, D.; Xiong, G.; Feng, H.; Zhang, Z.; Chen, P.; Yan, B.; Chen, L.; Gandhervin, K.; Ma, C.; Li, C.; et al. Donation of mitochondria by iPSC-derived mesenchymal stem cells protects retinal ganglion cells against mitochondrial complex I defect-induced degeneration. Theranostics 2019, 9, 2395–2410.
Vinores, S.A. Assessment of blood-retinal barrier integrity. Histol. Histopathol. 1995, 10, 141–154.
Singhal, S.; Lawrence, J.M.; Bhatia, B.; Ellis, J.S.; Kwan, A.S.; Macneil, A.; Luthert, P.J.; Fawcett, J.W.; Perez, M.T.; Khaw, P.T.; et al. Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted Muller stem cells into degenerating retina. Stem. Cells 2008, 26, 1074–1082.
Johnson, T.V.; Bull, N.D.; Martin, K.R. Identification of barriers to retinal engraftment of transplanted stem cells. Investig. Ophthalmol. Vis. Sci. 2010, 51, 960–970.
Nishida, A.; Takahashi, M.; Tanihara, H.; Nakano, I.; Takahashi, J.B.; Mizoguchi, A.; Ide, C.; Honda, Y. Incorporation and differentiation of hippocampus-derived neural stem cells transplanted in injured adult rat retina. Investig. Ophthalmol. Vis. Sci. 2000, 41, 4268–4274.
Yao, J.; Tucker, B.A.; Zhang, X.; Checa-Casalengua, P.; Herrero-Vanrell, R.; Young, M.J. Robust cell integration from co-transplantation of biodegradable MMP2-PLGA microspheRes with retinal progenitor cells. Biomaterials 2011, 32, 1041–1050.
Zhai, X.; Chen, K.; Yang, H.; Li, B.; Zhou, T.; Wang, H.; Zhou, H.; Chen, S.; Zhou, X.; Wei, X.; et al. Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury. J. Nanobiotechnol. 2021, 19, 274.
Li, K.; Zhong, X.; Yang, S.; Luo, Z.; Li, K.; Liu, Y.; Cai, S.; Gu, H.; Lu, S.; Zhang, H.; et al. HiPSC-derived retinal ganglion cells grow dendritic arbors and functional axons on a tissue-engineered scaffold. Acta Biomater. 2017, 54, 117–127.
Roozafzoon, R.; Lashay, A.; Vasei, M.; Ai, J.; Khoshzaban, A.; Keshel, S.H.; Barabadi, Z.; Bahrami, H. Dental pulp stem cells differentiation into retinal ganglion-like cells in a three dimensional network. Biochem. Biophys. Res. Commun. 2015, 457, 154–160.
Lamichhane, T.N.; Sokic, S.; Schardt, J.S.; Raiker, R.S.; Lin, J.W.; Jay, S.M. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine. Tissue Eng. Part B Rev. 2015, 21, 45–54.
Lai, R.C.; Arslan, F.; Lee, M.M.; Sze, N.S.; Choo, A.; Chen, T.S.; Salto-Tellez, M.; Timmers, L.; Lee, C.N.; El Oakley, R.M.; et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem. Cell. Res. 2010, 4, 214–222.
Desrochers, L.M.; Antonyak, M.A.; Cerione, R.A. Extracellular Vesicles: Satellites of Information Transfer in Cancer and Stem Cell Biology. Dev Cell. 2016, 37, 301–309.
Suzuki, E.; Fujita, D.; Takahashi, M.; Oba, S.; Nishimatsu, H. Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease. World J. Stem. Cells 2016, 8, 297–305.
Shen, B.; Liu, J.; Zhang, F.; Wang, Y.; Qin, Y.; Zhou, Z.; Qiu, J.; Fan, Y. CCR2 Positive Exosome Released by Mesenchymal Stem Cells Suppresses Macrophage Functions and Alleviates Ischemia/Reperfusion-Induced Renal Injury. Stem. Cells Int. 2016, 2016, 1240301.
Conforti, A.; Scarsella, M.; Starc, N.; Giorda, E.; Biagini, S.; Proia, A.; Carsetti, R.; Locatelli, F.; Bernardo, M.E. Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem. Cells Dev. 2014, 23, 2591–2599.
Burrello, J.; Monticone, S.; Gai, C.; Gomez, Y.; Kholia, S.; Camussi, G. Stem Cell-Derived Extracellular Vesicles and Immune-Modulation. Front Cell. Dev. Biol. 2016, 4, 83.
Favaro, E.; Carpanetto, A.; Lamorte, S.; Fusco, A.; Caorsi, C.; Deregibus, M.C.; Bruno, S.; Amoroso, A.; Giovarelli, M.; Porta, M.; et al. Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia 2014, 57, 1664–1673.
Blazquez, R.; Sanchez-Margallo, F.M.; de la Rosa, O.; Dalemans, W.; Alvarez, V.; Tarazona, R.; Casado, J.G. Immunomodulatory Potential of Human Adipose Mesenchymal Stem Cells Derived Exosomes on in vitro Stimulated T Cells. Front. Immunol. 2014, 5, 556.
Li, L.; Jin, S.; Zhang, Y. Ischemic preconditioning potentiates the protective effect of mesenchymal stem cells on endotoxin-induced acute lung injury in mice through secretion of exosome. Int. J. Clin. Exp. Med. 2015, 8, 3825–3832.
Zhang, Y.; Chopp, M.; Zhang, Z.G.; Katakowski, M.; Xin, H.; Qu, C.; Ali, M.; Mahmood, A.; Xiong, Y. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem. Int. 2017, 111, 69–81.
Chen, K.H.; Chen, C.H.; Wallace, C.G.; Yuen, C.M.; Kao, G.S.; Chen, Y.L.; Shao, P.L.; Chen, Y.L.; Chai, H.T.; Lin, K.C.; et al. Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke. Oncotarget 2016, 7, 74537–74556.
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.

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Xiteng Chen

Yuanfeng Jiang

Yanan Duan

Xiaomin Zhang

Xiaorong Li

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Update Date: 09 Jan 2023

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