You're using an outdated browser. Please upgrade to a modern browser for the best experience.
MSC-EVs in Osteoporosis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cimb44120433

Osteoporosis (OP) is a chronic bone disease characterized by decreased bone mass, destroyed bone microstructure, and increased bone fragility. Accumulative evidence shows that extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes (Exos), exhibit great potential in the treatment of OP.

osteoporosis extracellular vesicles exosomes miRNAs mesenchymal stem cells

1. Introduction

Osteoporosis (OP) is a systemic bone disease characterized by weakened bone structure strength, decreased bone mass, and increased fracture risk [1]. Due to the high rate of disability, morbidity, and mortality, OP causes a heavy burden to patients’ families and society, which is a major public health problem [2]. OP can be divided into primary OP and secondary OP. Primary OP is a systemic skeletal disease closely related to postmenopausal estrogen deficiency or age [3], while secondary OP refers to adverse reactions to drugs, changes in physical activity, or other diseases, such as glucocorticoids and restricted activity [4]. Under physiological and pathological conditions such as estrogen deficiency, aging, disuse, drug, and malnutrition, bone formation and bone absorption are decoupled or/and osteoblast differentiation and adipocyte differentiation of bone marrow mesenchymal stem cells (BMSCs) are unbalanced, which often leads to the occurrence and development of OP [5]. Therefore, coordinating osteoclastic–blastic coupling or osteo-adipogenic balance is an effective way to prevent and treat OP.
As an important member of the stem cell family, MSCs not only have the potential of self-renewal and multi-directional differentiation, including osteoblasts, chondrocytes, and adipocytes, but also have the characteristics of promoting angiogenesis, anti-inflammation, anti-apoptosis, and immune regulation. Therefore, MSCs are the most commonly used cell type in tissue engineering strategies [6]. Cumulative studies have shown that MSCs change the microenvironment of damaged tissues and repair damaged tissues mainly through paracrine action, rather than self-proliferation and differentiation to replace damaged tissues [7][8][9]. However, MSCs-based cell therapy still has some limitations, including invasive collection, a small amount of isolated cells, age dependency [10], immune rejection, and acquired gene mutation [11]. Recent studies have found that extracellular vesicles (EVs) are the key paracrine factors released by MSCs [12]. MSC-EVs contain many nucleic acids, proteins, lipids, and genetic molecules from parent cells, such as messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). MSC-EVs can mediate intercellular communication and regulate the cellular behavior of receptor cells by delivering encapsulated bioactive components [13]. In addition, MSC-EVs also have therapeutic functions similar to those of their parent stem cells, such as repairing damaged tissues, inhibiting inflammatory response, and regulating immune response [14]. Compared with MSCs transplantation, the cell-free therapy based on MSC-EVs has the advantages of low immunogenicity, non-tumorigenicity, non-vascular thrombosis, easy preservation, easy acquisition, and transformation [15]. Moreover, the unique lipid bilayer structure of EVs ensures stable cargo transport and protects biological molecules such as RNA from rapid degradation [16]. Importantly, MSC-EVs can be manipulated and genetically modified to improve the delivery efficiency of bioactive molecules [17]. In recent years, MSC-EVs-based strategies have been extensively studied in tissue regeneration and disease treatment [18]. BMSC-EVs overexpressing mutant hypoxia inducible factor-1α (HIF-1α) enhanced the therapeutic effect of steroid-induced femoral head necrosis in rabbit models [19]; BMSC-EVs can promote fracture healing [20]. The above research lay a foundation for the research on the prevention and treatment of OP by MSC-EVs. Although preliminary studies have shown that the cell-free therapy based on MSC-EVs is a promising therapeutic strategy for OP [21][22][23][24][25]; however, the research on MSC-EVs in treating OP is still in its early stage. Deeply understanding the potential mechanism of MSC-EVs regulating OP contributes to formulating more effective treatment strategies. By reviewing the relevant research literature on MSC-EVs and OP, researchers summarized the bone targeting effect of engineered MSC-EVs in OP and the potential mechanism of MSC-EVs regulating OP, providing a basis for clinical application research of MSC-EVs in OP.

2. Mechanisms of MSC-EVs in OP

Cumulative studies have shown that MSC-EVs can influence downstream signaling cascades by directly translocating their internal cargoes, which in turn regulate bone formation, bone resorption, bone angiogenesis, and immune activity in OP [26][27] (as shown in Figure 1). There are many endogenous molecules encapsulated within MSC-EVs. Among them, miRNAs, one of the major bioactive substances in EVs, are the most attractive bioactive molecules [28]. miRNAs are small endogenous non-coding single-stranded RNAs of 18~25 nucleotides in length [29] that can induce changes in a variety of cellular processes, including cell proliferation, differentiation, senescence, and apoptosis [30]. However, the instability of miRNAs in the extracellular environment limits their application. EVs act as a special membrane vesicle capable of protecting miRNAs from degradation and delivering miRNAs to target cells, thus regulating cell-cell communication. Accumulating evidence suggests that MSC-EV-miRNAs play an important role in the treatment of OP. MiR-935, miR-21-5p, miR-27a-5p [24][25][31], miR-31a-5p [32], miR-29a [33], miR-146a [34] encapsulated in MSC-EVs were shown to be involved in the regulation of bone formation, bone resorption, angiogenesis, and immunomodulatory effect. An in-depth understanding of the specific mechanisms of MSC-EVs in OP would be beneficial to facilitate clinical translational research on MSC-EVs in OP.
Figure 1. Mechanisms of MSC-EVs regulating the osteogenic differentiation in OP.

2.1. Regulation of Bone Formation by MSC-EVs in OP

Bone remodeling consists of two processes: osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disruption of the homeostasis of bone remodeling may lead to OP. There is growing evidence that the crosstalk between monocyte-macrophage-osteoclasts and MSC-osteoblasts plays a crucial role in the pathological changes of OP [35]. Osteoblasts are derived from the osteogenic differentiation of MSCs [36], which is influenced by many environmental factors, such as hormones and growth factors [37]. A previous study confirmed the critical role of human bone marrow mesenchymal stem cell (hBMSC) osteogenic differentiation for bone regeneration therapy and the bone regenerative potential of hBMSC-EVs [38]. Importantly, human umbilical cord MSCs (HucMSCs)-derived Exos significantly promoted osteoblast differentiation and showed therapeutic effects in OVX mice [39]. Multiple bone formation-related signaling pathways have been identified to mediate the regulation of OP by MSC-Exos, such as Wnt/β-catenin, Hippo, phosphoinositide 3-kinase (PI3K)/Akt, nuclear factor kappa-B (NF-κB), and special AT-rich sequence-binding protein 2 (SATB2). Further understanding of the underlying mechanisms of osteogenic differentiation is essential for the development of effective therapeutic strategies for OP.

2.1.1. Wnt/β-Catenin Signaling Mediates MSC-EVs Regulating Bone Formation in OP

Previous studies have confirmed that the Wnt signaling pathway can regulate the bone remodeling process by affecting both bone formation and bone resorption, thus participating in the initiation and development of OP [40]. The Wnt signaling pathway includes both classical and non-classical pathways. β-catenin protein, as a key signaling factor in the classical Wnt pathway, stimulates osteoblast differentiation and proliferative activity, which is most closely related to bone metabolism [41]. The classical Wnt/β-catenin signaling pathway mainly includes: ligand (Wnt extracellular protein), frizzled transmembrane receptor (Frizzled), receptor-related protein 5/6 (LRP-5/6), glycogen synthase kinase-3β (GSK-3β), and Axin. Studies have shown that the Wnt/β-catenin signaling pathway enhances osteoblast activity mainly by regulating the expression of osteogenic differentiation-specific genes, thereby promoting extracellular matrix mineralization to enhance bone formation and regulate bone remodeling [42]. Recent studies have demonstrated that MSC-EVs can promote osteoblast proliferation and differentiation, which may be closely related to Wnt/β-catenin signaling. Gong et al. [43] demonstrated the positive role of human embryonic stem cell-derived EVs (hESC-EVs) in reversing the senescence of BMSCs and promoting the proliferation and osteogenic differentiation potential of BMSCs through the transfer of encapsulated proteins. Bioinformatics analysis further revealed that protein components in hESC-EVs activate several classical signaling pathways involved in alleviating cellular senescence and promoting osteogenesis, including Wnt/β-catenin, which are involved in regulating the expression of anti-senescence genes to ameliorate MSCs senescence and promote osteogenic differentiation, either through direct or indirect interactions, or through synergistic interactions. It is suggested that Wnt/β-catenin signaling pathway may be involved in the regulatory role of EVs on OP. Unfortunately, the study did not further validate this. Since then, many scholars have further validated the role of Wnt/β-catenin signaling pathway in OP. Peng et al. [44] reported that BMSC-Exos can deliver the intrinsic miR-196a targeting to inhibit dickkopf-1 (DKK1), a negative regulator of the Wnt/β-catenin signaling pathway, to activate the Wnt/β-catenin signaling pathway, ultimately promoting osteogenic differentiation. In addition, miR-27, considered a key mediator of osteoblast differentiation, could promote reosseointegration in the regenerative treatment of peri-implantitis by directly targeting DKK2 [45]. Wang et al. [46] found that MSC-EVs had a similar protective effect on OP as miR-27a, while miR-27a inhibitor partially reversed the protective effect of MSC-EVs on OP. In contrast, knockdown of DKK2 reversed the inhibitory effect of miR-27a inhibitors on OP. Further studies revealed that miR-27a released from MSC-EVs positively regulated bone formation through the DKK2/Wnt/β-catenin signaling pathway, thereby effectively preventing OP in mice [46], although the above studies illustrate that unmodified MSC-EVs promote osteogenic differentiation through the Wnt/β-catenin signaling pathway. However, unmodified MSC-EVs showed limited therapeutic effects on OP. Previous studies have reported glycoprotein non-melanoma clone B (GPNMB) as a multifunctional transmembrane glycoprotein that plays a key role in osteoblast differentiation and bone homeostasis [47]. Huang et al. [48] explored the respective effects on OP by constructing BMSC-EVs overexpressing GPNMB compared to unmodified BMSC-EVs. The team found that GPNMB-modified BMSC-EVs were more effective in treating OP than unmodified BMSC-EVs. Mechanistically, BMSC-EVs significantly promoted the proliferation and osteogenic differentiation of BMSCs and reduced bone loss by activating the Wnt/β-catenin signaling pathway. In addition, studies have also identified a negative role of Wnt/β-catenin signaling in the treatment of OP by MSC-EVs. MiR-424-5p, one of the core miRNAs for tension-induced bone formation, is associated with pathological changes in osteosclerosis [49]. The Wnt inhibitor WIF-1 is a member of the Wnt protein secretion regulators that interacts directly with various Wnt ligands and attenuates their binding to membrane-bound receptors [50]. Wei et al. [51] revealed that BMSC-Exos overexpressing miR-424-5p inhibited osteogenic differentiation by suppressing the WIF1/Wnt/β-catenin signaling axis, while WIF1 overexpression partially reversed the osteogenic inhibitory effect of BMSC-Exos, indicating that interfering with miRNAs in MSC-Exos may be a new direction for the treatment of OP.
In summary, the Wnt/β-catenin signaling pathway is one of the important mechanisms involved in the treatment of MSC-EVs in OP. The promotion or inhibition of bone formation by the Wnt/β-catenin signaling pathway is influenced by the modification of MSC-EVs or the type of miRNAs in MSC-EVs. In addition to miRNAs, MSC-EVs contain many proteins, lipids, and other types of nucleic acids. Therefore, other intrinsically bioactive molecules derived from MSC-EVs, such as lncRNAs and circular RNAs (circRNAs), may also regulate OP through the Wnt/β-catenin signaling pathway, which requires further exploration.

2.1.2. Hippo Signaling Mediates MSC-EVs Regulating Bone Formation in OP

Hippo signaling, consisting of an articulated protein and an inhibitory kinase, was first identified in Drosophila. Hippo signaling is a highly conserved signaling pathway between Drosophila and mammals [52]. The classical Hippo signaling pathway is functioned by the kinases MST1/2 and LATS1/2 that phosphorylate with SAV1 and Mob1 and inhibit the transcriptional coactivators YAP and TAZ [53]. It was found that the Hippo signaling pathway induces osteogenic differentiation of MSCs by upregulating the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Osterix through the binding of the WW structural domain of TAZ to the PY motif of Runx2 [54]. Recent studies have found that Hippo signaling may also play a role in the treatment of OP by MSC-EVs. Yang et al. [55] explored the role of HucMSC-Exos in the regulation of proliferation and apoptosis of BMSCs in a rat model of disuse OP (DOP). This study found that in DOP, the expression of Mob1 was upregulated, which inhibited the activation of YAP and activated the Hippo signaling pathway. Interestingly, miRNA-1263 can inhibit Mob1 expression to reactivate the repressed YAP and directly impede the Hippo signaling pathway, thereby inhibiting BMSC apoptosis and promoting osteogenic differentiation in DOP. It is suggested that miR-1263 regulates apoptosis and osteogenic differentiation of BMSCs through the Mob1/Hippo signaling pathway. In addition, Li et al. [56] explored the effect of hBMSC-Exo-miR-186 on postmenopausal OP. Mob1, a cofactor that regulates YAP, is a potential target of miR-186 [57]. This study found that hBMSC-Exos and miR-186 mimics promoted the expression of YAP, while miR-186 inhibitors decreased the expression of YAP and Mob1. Further studies revealed that hBMSC-Exos or miR-186 mimics increased bone volume in OVX rats, while miR-186 inhibitors decreased bone volume. It suggests that hBMSC-Exos promotes bone formation in OVX rats through the Hippo signaling pathway by transferring the intrinsic miR-186.
The above studies illustrate the positive role of the Hippo signaling pathway in the treatment of OP by MSC-EVs. Notably, the Hippo signaling pathway forms a sophisticated molecular regulatory network around the upstream protein kinase MST1/2 and the downstream effector molecule YAP/TAZ, which have important roles in maintaining normal physiological functions of bone. However, there is no consensus on the complex regulatory mechanisms of MST1/2 and YAP/TAZ. Further exploration of the series of molecular events of MST1/2, YAP/TAZ and their upstream and downstream transcription factors is necessary to provide new ideas for related studies of OP.

2.1.3. PI3K/Akt Signaling Mediates MSC-EVs Regulating Bone Formation in OP

PI3K/Akt signaling is closely associated with cell proliferation, differentiation, and apoptosis in many tissues [58]. Upon stimulation by growth factors, PI3K is activated to produce phosphatidylinositol trisphosphate, which binds to Akt to translocate Akt from the cytoplasm to the cell membrane while undergoing a conformational change. Subsequently, Akt is activated and further activates downstream target genes to participate in cell growth and differentiation [59]. Previous studies have found that the PI3K/Akt signaling pathway plays an important role in bone formation by regulating the potential and direction of early BMSC differentiation [60]. Lu et al. [61] analyzed the changes in mRNA expression profiles in bone tissue of OVX mice treated with or without MSC-EVs by the next-generation sequencing (NGS) technique to identify the key intrinsic cargoes and the key signaling pathways involved in the treatment of OP with MSC-EVs. This study found that MSC-EVs may exert their therapeutic effects on OP by upregulating extracellular matrix-associated gene expression and activating the PI3K/Akt signaling pathway through the intrinsic miRNAs, including miR-21, miR-29, and miR-221. However, the specific mechanism still needs to be further explored. Furthermore, Zhang et al. [62] explored in depth the possible regulatory mechanism of miR-22-3p loaded by MSC-EVs on bone formation in OP by loss and gain of function experiments. The results revealed that overexpression of miR-22-3p encapsulated in MSC-EVs could upregulate the expression of osteogenic genes such as Runx2, osteocalcin (OCN), and osteopontin (OPN) and enhance ALP activity and matrix mineralization in BMSCs by directly targeting alpha-ketoglutarate-dependent dioxygenase FTO (FTO), whereas miR-22-3p inhibitor could repress osteogenic differentiation of BMSCs, which may be closely related to the MYC/PI3K/Akt pathway. Further studies showed that FTO silencing could partially reverse the inhibition of osteogenic differentiation caused by miR-22-3p inhibitors [62]. It suggests that MSC-EV-miR-22-3p can promote osteogenic differentiation via the MYC/PI3K/Akt pathway.
In summary, multiple miRNAs encapsulated in MSC-EVs, including miR-21, miR-29, miR-221, and miR-22-3p, can promote osteogenic differentiation in OP via the PI3K/Akt signaling pathway. However, EV-miRNAs have a complicated readout in both physiological and pathophysiological states. For the detected miRNAs, the conclusions obtained are usually unreliable due to the presence of most EV-miRNAs universally expressed making it difficult to trace the specific tissues in which they function. Therefore, tissue-specific miRNAs should be considered to provide a clear demonstration of the specific roles of certain miRNAs in the future.

2.2. Regulation of Bone Resorption by MSC-EVs in OP

Osteoclasts, the main effector cells of bone resorption, play a crucial role in skeletal development and in the pathogenesis of bone diseases [63]. Osteoclasts are derived from the monocyte/macrophage lineage, which can enhance bone resorption activity by secreting acidic substances and proteases. The relative enhancement of osteoclast activity is the key cause of OP [64]. Previous studies found that BMSC-EVs transfer intrinsic miR-143/145 to osteoblasts to trigger osteoclast activity and differentiation by targeting Cd226 and Srgap2 [65]. Furthermore, Chen et al. [66] found that osteoclast-associated genes such as Trap, MMP9, and Ctsk were repressed in OP mice treated with human urine-derived stem cells (USCs)-Exos and confirmed that collagen triple-helix repeat loaded in Exos-containing 1 (CTHRC1) and osteoprotegerin (OPG) proteins in Exos inhibited osteoclastogenesis. RANKL, as a member of the RANK/RANKL pathway, is essential in regulating bone remodeling [67]. RANKL secreted by osteoblasts binds to the receptor RANK on the surface of osteoclasts and their precursor cells to promote osteoclast survival and stimulate osteoblast maturation, proliferation, and differentiation [68]. Ren et al. [69] found that Exos derived from adipose-derived stem cells (ADSCs) inhibited RANKL expression at the mRNA and protein levels and reduced the RANKL/OPG ratio, thereby improving osteocyte-mediated osteoclastogenesis in vitro. Moreover, Hu et al. [5] revealed that the potently pro-osteogenic protein, CLEC11A (C-type lectin domain family 11, member A) encapsulated by HucMSC-EVs inhibits osteoclastogenesis by suppressing RANKL expression, thereby alleviating OP. OPG is a soluble protein that binds to RANKL to prevent RANKL from activating RANK. Lee et al. [70] found that ADSC-EVs significantly inhibited the differentiation of macrophages to osteoclasts and promoted the migration of BMSCs, which in turn attenuated bone loss in OP mice. However, OPG-deficient ADSC-EVs did not exhibit an anti-osteoclastogenic effect. Further studies revealed that OPG in ADSC-EVs was involved in inhibiting osteoclast differentiation and reducing the expression of genes related to bone resorption [70]. The above studies suggest that OPG/RANKL/RANK signaling may be involved in cell-free therapy of OP by ADSC-EVs. Furthermore, Xiao et al. [71] constructed hindlimb unloading-induced DOP mouse models to compare cyclic mechanical stretch (CMS)-treated BMSC-Exos (CMS-Exos) and normal static-cultured BMSC-Exos (static-Exos) in DOP. The results showed that although both CMS-Exos and static-Exos partially rescued mechanical unloading-induced OP, the CMS-Exo group exhibited a more significant therapeutic effect. Mechanistically, CMS-Exos impairs osteoclast differentiation by inhibiting the activity of the RANKL-induced NF-κB signaling pathway and ameliorates bone loss induced by mechanical unloading in a hindlimb unloading DOP mouse model. In addition, another study found that miR-27a released from MSC-EVs can inhibit osteoclast differentiation through the DKK2/Wnt/β-catenin signaling pathway [46]. In contrast, one study revealed that aged rat BMSC-Exo-miR-31a-5p positively regulates osteoclastogenesis by targeting RhoA signaling, thereby exacerbating OP [32].
In summary, MSC-EVs can inhibit osteoclastogenesis via OPG/RANKL/RANK, NF-κB, and Wnt/β-catenin signaling pathways, whereas the RhoA signaling pathway exerted the opposite effect on osteoclastogenesis, depending on whether the parental cells of EVs were derived from normal or senescent MSCs (As shown in Figure 2). Notably, CMS-Exos treatment, but not static-Exos, improves cortical bone loss in OP [71]. It may be that mechanical stimulation alters the intrinsic cargo composition of EVs to confer stronger anti-OP activity to EVs, indicating that the therapeutic effect of EVs can be enhanced by modulating the parental cell microenvironment.
Figure 2. Mechanisms of MSC-EVs regulating the osteoclastogenesis in OP.

2.3. Regulation of Bone Angiogenesis by MSC-EVs in OP

Angiogenesis is of great importance for bone reconstruction. On the one hand, it provides bone tissue with the required oxygen and nutrients; on the other hand, it provides calcium and phosphate to facilitate bone mineralization. Impaired angiogenesis predisposes to impaired bone regeneration, which is one of the major causes of OP [72]. An important vascular subtype (type-H vessels) was found to regulate the growth of the bone vascular system, recruit osteogenic progenitor cells, and integrate osteogenesis and angiogenesis [73]. Stimulation of type-H vessel formation can partially rescue bone loss [74]. Cumulative studies have found that MSC-EVs are enriched in platelet-derived growth factor, epidermal growth factor, fibroblast growth factor, and NF-κB signaling axis-related proteins. NF-κB is a key mediator of endothelial cell angiogenesis induced by MSC-EVs. It suggests that MSC-EVs contain many pro-angiogenic paracrine effector molecules [75]. Qi et al. [76] first reported that iMSC-Exos can promote bone regeneration by enhancing angiogenesis and osteogenesis in OP rats, indicating that iMSC-Exos has the potential to promote angiogenesis in OP. Subsequently, an Exos delivery system based on iPSC-MSC-Exos was developed to silence the SHN3 gene in osteoblasts and promote the production of the proangiogenic factor slit guidance ligand 3 (SLIT3), which increases type-H vessel formation and thus alleviates OP [77]. In addition, Lu et al. [33] found that BMSC-Exos could be taken up by human umbilical vein endothelial cells (HUVECs) and promoted the proliferation, migration, and tube formation of HUVECs, ultimately promoting angiogenesis and improving OP symptoms in OP mouse models. Further analysis revealed that miR-29a loaded in BMSC-Exos promotes angiogenesis by directly targeting inhibition of VASH1. In addition, Behera et al. [78] identified a bone-specific lncRNA H19 in BMSC-Exos by sequencing analysis and subsequently evaluated the effect of BMSC-Exos on angiogenesis in an immunodeficient cystathionine β-synthase (CBS)-heterozygous mouse model. This study revealed that lncRNA H19 in BMSC-Exos targeted repression of miR-106 expression through molecular sponge action and negatively regulated the expression of angiogenic factor Angpt1. Subsequently, reduction of Angpt1 in endothelial cells further activates Tie2-NO signaling and ultimately significantly promotes angiogenesis in CBS-heterozygous mice.
In summary, MSC-EVs demonstrated their great potential to promote angiogenesis in OP (As shown in Figure 3). However, the specific mechanisms involved are still unclear and further studies are needed. Furthermore, although miR-29a and lncRNA H19 loaded in MSC-EVs have been found to play a crucial role in regulating angiogenesis, other bioactive molecules encapsulated in MSC-EVs may also be involved in the regulation of angiogenesis by MSC-EVs in OP. Further screening of other potential key components in MSC-EVs to regulate angiogenesis is required in OP.
Figure 3. Mechanisms of MSC-EVs regulating the angiogenesis in OP.

2.4. Regulation of Bone Immunity by MSC-EVs in OP

Previous studies have shown that OP is closely related to the immune inflammatory system. The activation of the immune system and the release of inflammatory factors play an important role in the initiation and development of OP [79]. The activation and proliferation of immune inflammatory cells, mainly T lymphocytes, leads to the release of inflammatory factors such as interleukin-1β (IL-1β) and TNF-α and promotes osteoclast formation, which exacerbates bone resorption [80]. MSC-EVs have been shown to have a wide range of immunomodulatory effects, including suppressing T lymphocyte activity and promoting apoptosis, inhibiting inflammatory factor secretion, reducing neutrophil aggregation, inducing conversion of Th1 to Th2 cell type, and reducing the potential for T cell differentiation to Th17 cell type [81][82]. Therefore, MSC-EVs may play an immunomodulatory role in the treatment of OP. Zhang et al. [83] explored the effects of ADSC-Exos on cellular and animal models of diabetic OP constructed by high glucose exposure and streptozotocin injection. It was found that ADSC-Exos inhibited high glucose-induced secretion of secretion of IL-1β and IL-18 by osteoclasts, decreased the expression and activation of NLRP3 inflammasome-associated proteins (included pro-caspase-1, sensor protein NLRP3, and adaptor protein ASC) and restored bone loss in diabetic osteoporotic rats. Mechanistically, ADSC-Exos inhibited the activation of NLRP3 inflammasome in osteoclasts and reduced the production of inflammatory mediators including TNF-α, IL-6, PGE2, and NO, which in turn reduced bone resorption and restored bone loss [83], suggesting that ADSC-Exos may be a potential cell-free therapeutic strategy for diabetic bone loss. In addition, studies have reported miR-146a as a core mediator in the anti-inflammatory action of Exos [84]. To investigate the role of MSC-Exo-miR-146a in the treatment of diabetic OP, Zhang et al. [34] extracted miR-146a-enriched Exos from ADSCs overexpressing miR-146a to explore its protective effect against osteoclast inflammation. The results revealed that miR-146a-Exos had more potent inhibitory effect than Exos/vector-Exos in reducing the expression and secretion of pro-inflammatory cytokines such as TNF-α, IL-18, and IL-1β in osteoclasts and bone resorption in vivo and vitro. Moreover, the anti-inflammation effect of miR-146a has been reported in other cellular and animal models, and Exos with overexpressed miR-146a was able to magnify the anti-inflammation effect. Overall, ADSC-Exo-miR-146a could effectively inhibit the expression of pro-inflammatory cytokines, secreted by osteoclasts induced by high glucose, induce the inflammasome inactivation, inhibit bone resorption, and ultimately restore bone loss in diabetic osteoporotic rats, indicating that ADSC-Exo-miR-146a can effectively inhibit the inflammatory response of osteoclasts and provide a potential strategy for the treatment of diabetic OP.

References

  1. Compston, J.E.; McClung, M.R.; Leslie, W.D. Osteoporosis. Lancet 2019, 393, 364–376.
  2. Kanis, J.A.; Cooper, C.; Rizzoli, R.; Reginster, J.Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos. Int. 2019, 30, 3–44.
  3. Brown, C. Osteoporosis: Staying strong. Nature 2017, 550, S15–S17.
  4. Owen, R.; Reilly, G.C. In vitro Models of Bone Remodelling and Associated Disorders. Front. Bioeng. Biotechnol. 2018, 6, 134.
  5. Hu, Y.; Zhang, Y.; Ni, C.Y.; Chen, C.Y.; Rao, S.S.; Yin, H.; Huang, J.; Tan, Y.J.; Wang, Z.X.; Cao, J.; et al. Human umbilical cord mesenchymal stromal cells-derived extracellular vesicles exert potent bone protective effects by CLEC11A-mediated regulation of bone metabolism. Theranostics 2020, 10, 2293–2308.
  6. Wei, D.X.; Dao, J.W.; Chen, G.Q. A Micro-Ark for Cells: Highly Open Porous Polyhydroxyalkanoate Microspheres as Injectable Scaffolds for Tissue Regeneration. Adv. Mater. 2018, 30, e1802273.
  7. Li, Y.; Wang, J.; Ma, Y.; Du, W.; Feng, K.; Wang, S. miR-101-loaded exosomes secreted by bone marrow mesenchymal stem cells requires the FBXW7/HIF1α/FOXP3 axis, facilitating osteogenic differentiation. J. Cell. Physiol. 2021, 236, 4258–4272.
  8. Rosner, M.; Pham, H.T.T.; Moriggl, R.; Hengstschläger, M. Human stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1. Nat. Commun. 2017, 8, 595.
  9. Johnston, A.P.; Yuzwa, S.A.; Carr, M.J.; Mahmud, N.; Storer, M.A.; Krause, M.P.; Jones, K.; Paul, S.; Kaplan, D.R.; Miller, F.D. Dedifferentiated Schwann Cell Precursors Secreting Paracrine Factors Are Required for Regeneration of the Mammalian Digit Tip. Cell Stem Cell 2016, 19, 433–448.
  10. Xie, Y.; Hu, J.H.; Wu, H.; Huang, Z.Z.; Yan, H.W.; Shi, Z.Y. Bone marrow stem cells derived exosomes improve osteoporosis by promoting osteoblast proliferation and inhibiting cell apoptosis. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 1214–1220.
  11. Jiang, L.B.; Tian, L.; Zhang, C.G. Bone marrow stem cells-derived exosomes extracted from osteoporosis patients inhibit osteogenesis via microRNA-21/SMAD7. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 6221–6229.
  12. Aghebati-Maleki, L.; Dolati, S.; Zandi, R.; Fotouhi, A.; Ahmadi, M.; Aghebati, A.; Nouri, M.; Kazem Shakouri, S.; Yousefi, M. Prospect of mesenchymal stem cells in therapy of osteoporosis: A review. J. Cell. Physiol. 2019, 234, 8570–8578.
  13. Jung, Y.J.; Kim, H.K.; Cho, Y.; Choi, J.S.; Woo, C.H.; Lee, K.S.; Sul, J.H.; Lee, C.M.; Han, J.; Park, J.H.; et al. Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes. Sci. Adv. 2020, 6, eaay6721.
  14. Woo, C.H.; Kim, H.K.; Jung, G.Y.; Jung, Y.J.; Lee, K.S.; Yun, Y.E.; Han, J.; Lee, J.; Kim, W.S.; Choi, J.S.; et al. Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration. J. Extracell. Vesicles 2020, 9, 1735249.
  15. Ingato, D.; Lee, J.U.; Sim, S.J.; Kwon, Y.J. Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery. J. Control. Release 2016, 241, 174–185.
  16. El Andaloussi, S.; Mäger, I.; Breakefield, X.O.; Wood, M.J. Extracellular vesicles: Biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 2013, 12, 347–357.
  17. Phan, J.; Kumar, P.; Hao, D.; Gao, K.; Farmer, D.; Wang, A. Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy. J. Extracell. Vesicles 2018, 7, 1522236.
  18. Maqsood, M.; Kang, M.; Wu, X.; Chen, J.; Teng, L.; Qiu, L. Adult mesenchymal stem cells and their exosomes: Sources, characteristics, and application in regenerative medicine. Life Sci. 2020, 256, 118002.
  19. Li, H.; Liu, D.; Li, C.; Zhou, S.; Tian, D.; Xiao, D.; Zhang, H.; Gao, F.; Huang, J. Exosomes secreted from mutant-HIF-1α-modified bone-marrow-derived mesenchymal stem cells attenuate early steroid-induced avascular necrosis of femoral head in rabbit. Cell Biol. Int. 2017, 41, 1379–1390.
  20. Furuta, T.; Miyaki, S.; Ishitobi, H.; Ogura, T.; Kato, Y.; Kamei, N.; Miyado, K.; Higashi, Y.; Ochi, M. Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model. Stem Cells Transl. Med. 2016, 5, 1620–1630.
  21. Gatti, M.; Beretti, F.; Zavatti, M.; Bertucci, E.; Ribeiro Luz, S.; Palumbo, C.; Maraldi, T. Amniotic Fluid Stem Cell-Derived Extracellular Vesicles Counteract Steroid-Induced Osteoporosis In Vitro. Int. J. Mol. Sci. 2020, 22, 38.
  22. Qiu, M.; Zhai, S.; Fu, Q.; Liu, D. Bone Marrow Mesenchymal Stem Cells-Derived Exosomal MicroRNA-150-3p Promotes Osteoblast Proliferation and Differentiation in Osteoporosis. Hum. Gene Ther. 2021, 32, 717–729.
  23. Sonoda, S.; Murata, S.; Nishida, K.; Kato, H.; Uehara, N.; Kyumoto, Y.N.; Yamaza, H.; Takahashi, I.; Kukita, T.; Yamaza, T. Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model. Stem Cell Res. Ther. 2020, 11, 296.
  24. You, M.; Ai, Z.; Zeng, J.; Fu, Y.; Zhang, L.; Wu, X. Bone mesenchymal stem cells (BMSCs)-derived exosomal microRNA-21-5p regulates Kruppel-like factor 3 (KLF3) to promote osteoblast proliferation in vitro. Bioengineered 2022, 13, 11933–11944.
  25. Li, X.; Chen, R.; Li, Y.; Wang, P.; Cui, Y.; Yang, L.; Zhu, X.; Zhang, R. miR-27a-5p-Abundant Small Extracellular Vesicles Derived from Epimedium-Preconditioned Bone Mesenchymal Stem Cells Stimulate Osteogenesis by Targeting Atg4B-Mediated Autophagy. Front. Cell Dev. Biol. 2021, 9, 642646.
  26. Zhou, X.; Cao, H.; Guo, J.; Yuan, Y.; Ni, G. Effects of BMSC-Derived EVs on Bone Metabolism. Pharmaceutics 2022, 14, 1012.
  27. Lu, C.H.; Chen, Y.A.; Ke, C.C.; Liu, R.S. Mesenchymal Stem Cell-Derived Extracellular Vesicle: A Promising Alternative Therapy for Osteoporosis. Int. J. Mol. Sci. 2021, 22, 12750.
  28. Toh, W.S.; Lai, R.C.; Hui, J.H.P.; Lim, S.K. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin. Cell Dev. Biol. 2017, 67, 56–64.
  29. Seenprachawong, K.; Tawornsawutruk, T.; Nantasenamat, C.; Nuchnoi, P.; Hongeng, S.; Supokawej, A. miR-130a and miR-27b Enhance Osteogenesis in Human Bone Marrow Mesenchymal Stem Cells via Specific Down-Regulation of Peroxisome Proliferator-Activated Receptor γ. Front. Genet. 2018, 9, 543.
  30. Davis, H.M.; Pacheco-Costa, R.; Atkinson, E.G.; Brun, L.R.; Gortazar, A.R.; Harris, J.; Hiasa, M.; Bolarinwa, S.A.; Yoneda, T.; Ivan, M.; et al. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell 2017, 16, 551–563.
  31. Zhang, Y.; Cao, X.; Li, P.; Fan, Y.; Zhang, L.; Ma, X.; Sun, R.; Liu, Y.; Li, W. microRNA-935-modified bone marrow mesenchymal stem cells-derived exosomes enhance osteoblast proliferation and differentiation in osteoporotic rats. Life Sci. 2021, 272, 119204.
  32. Xu, R.; Shen, X.; Si, Y.; Fu, Y.; Zhu, W.; Xiao, T.; Fu, Z.; Zhang, P.; Cheng, J.; Jiang, H. MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment. Aging Cell 2018, 17, e12794.
  33. Lu, G.D.; Cheng, P.; Liu, T.; Wang, Z. BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis. Front. Cell Dev. Biol. 2020, 8, 608521.
  34. Zhang, L.; Wang, Q.; Su, H.; Cheng, J. Exosomes from Adipose Tissues Derived Mesenchymal Stem Cells Overexpressing MicroRNA-146a Alleviate Diabetic Osteoporosis in Rats. Cell. Mol. Bioeng. 2022, 15, 87–97.
  35. Deng, H.; Sun, C.; Sun, Y.; Li, H.; Yang, L.; Wu, D.; Gao, Q.; Jiang, X. Lipid, Protein, and MicroRNA Composition Within Mesenchymal Stem Cell-Derived Exosomes. Cell. Reprogram. 2018, 20, 178–186.
  36. Valenti, M.T.; Dalle Carbonare, L.; Mottes, M. Osteogenic Differentiation in Healthy and Pathological Conditions. Int. J. Mol. Sci. 2016, 18, 41.
  37. Faghihi, F.; Baghaban Eslaminejad, M. The effect of nano-scale topography on osteogenic differentiation of mesenchymal stem cells. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czechoslov. 2014, 158, 5–16.
  38. Martins, M.; Ribeiro, D.; Martins, A.; Reis, R.L.; Neves, N.M. Extracellular Vesicles Derived from Osteogenically Induced Human Bone Marrow Mesenchymal Stem Cells Can Modulate Lineage Commitment. Stem Cell Rep. 2016, 6, 284–291.
  39. Yahao, G.; Xinjia, W. The Role and Mechanism of Exosomes from Umbilical Cord Mesenchymal Stem Cells in Inducing Osteogenesis and Preventing Osteoporosis. Cell Transplant. 2021, 30, 9636897211057465.
  40. Rudiansyah, M.; El-Sehrawy, A.A.; Ahmad, I.; Terefe, E.M.; Abdelbasset, W.K.; Bokov, D.O.; Salazar, A.; Rizaev, J.A.; Muthanna, F.M.S.; Shalaby, M.N. Osteoporosis treatment by mesenchymal stromal/stem cells and their exosomes: Emphasis on signaling pathways and mechanisms. Life Sci. 2022, 306, 120717.
  41. Catalano, A.; Loddo, S.; Bellone, F.; Pecora, C.; Lasco, A.; Morabito, N. Pulsed electromagnetic fields modulate bone metabolism via RANKL/OPG and Wnt/β-catenin pathways in women with postmenopausal osteoporosis: A pilot study. Bone 2018, 116, 42–46.
  42. Maleki Dana, P.; Sadoughi, F.; Mansournia, M.A.; Mirzaei, H.; Asemi, Z.; Yousefi, B. Targeting Wnt signaling pathway by polyphenols: Implication for aging and age-related diseases. Biogerontology 2021, 22, 479–494.
  43. Gong, L.; Chen, B.; Zhang, J.; Sun, Y.; Yuan, J.; Niu, X.; Hu, G.; Chen, Y.; Xie, Z.; Deng, Z.; et al. Human ESC-sEVs alleviate age-related bone loss by rejuvenating senescent bone marrow-derived mesenchymal stem cells. J. Extracell. Vesicles 2020, 9, 1800971.
  44. Peng, Z.; Lu, S.; Lou, Z.; Li, Z.; Li, S.; Yang, K.; Li, C. Exosomes from bone marrow mesenchymal stem cells promoted osteogenic differentiation by delivering miR-196a that targeted Dickkopf-1 to activate Wnt/β-catenin pathway. Bioengineered 2021.
  45. Wu, X.; Gu, Q.; Chen, X.; Mi, W.; Wu, T.; Huang, H. MiR-27a targets DKK2 and SFRP1 to promote reosseointegration in the regenerative treatment of peri-implantitis. J. Bone Miner. Res. 2019, 34, 123–134.
  46. Wang, Y.; Zhou, X.; Wang, D. Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibit Osteoporosis via MicroRNA-27a-Induced Inhibition of DKK2-Mediated Wnt/β-Catenin Pathway. Inflammation 2022, 45, 780–799.
  47. Hu, H.; Li, Z.; Lu, M.; Yun, X.; Li, W.; Liu, C.; Guo, A. Osteoactivin inhibits dexamethasone-induced osteoporosis through up-regulating integrin β1 and activate ERK pathway. Biomed. Pharmacother. 2018, 105, 66–72.
  48. Huang, B.; Su, Y.; Shen, E.; Song, M.; Liu, D.; Qi, H. Extracellular vesicles from GPNMB-modified bone marrow mesenchymal stem cells attenuate bone loss in an ovariectomized rat model. Life Sci. 2021, 272, 119208.
  49. Wang, P.; Dong, R.; Wang, B.; Lou, Z.; Ying, J.; Xia, C.; Hu, S.; Wang, W.; Sun, Q.; Zhang, P.; et al. Genome-wide microRNA screening reveals miR-582-5p as a mesenchymal stem cell-specific microRNA in subchondral bone of the human knee joint. J. Cell. Physiol. 2019, 234, 21877–21888.
  50. Poggi, L.; Casarosa, S.; Carl, M. An Eye on the Wnt Inhibitory Factor Wif1. Front. Cell Dev. Biol. 2018, 6, 167.
  51. Wei, Y.; Ma, H.; Zhou, H.; Yin, H.; Yang, J.; Song, Y.; Yang, B. miR-424-5p shuttled by bone marrow stem cells-derived exosomes attenuates osteogenesis via regulating WIF1-mediated Wnt/β-catenin axis. Aging 2021, 13, 17190–17201.
  52. Ardestani, A.; Lupse, B.; Maedler, K. Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism. Trends Endocrinol. Metab. TEM 2018, 29, 492–509.
  53. Ma, S.; Meng, Z.; Chen, R.; Guan, K.L. The Hippo Pathway: Biology and Pathophysiology. Annu. Rev. Biochem. 2019, 88, 577–604.
  54. Yang, J.Y.; Cho, S.W.; An, J.H.; Jung, J.Y.; Kim, S.W.; Kim, S.Y.; Kim, J.E.; Shin, C.S. Osteoblast-targeted overexpression of TAZ increases bone mass in vivo. PLoS ONE 2013, 8, e56585.
  55. Yang, B.C.; Kuang, M.J.; Kang, J.Y.; Zhao, J.; Ma, J.X.; Ma, X.L. Human umbilical cord mesenchymal stem cell-derived exosomes act via the miR-1263/Mob1/Hippo signaling pathway to prevent apoptosis in disuse osteoporosis. Biochem. Biophys. Res. Commun. 2020, 524, 883–889.
  56. Li, L.; Zhou, X.; Zhang, J.T.; Liu, A.F.; Zhang, C.; Han, J.C.; Zhang, X.Q.; Wu, S.; Zhang, X.Y.; Lv, F.Q. Exosomal miR-186 derived from BMSCs promote osteogenesis through hippo signaling pathway in postmenopausal osteoporosis. J. Orthop. Surg. Res. 2021, 16, 23.
  57. Johnson, R.; Halder, G. The two faces of Hippo: Targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat. Rev. Drug Discov. 2014, 13, 63–79.
  58. Zhao, F.; Xu, Y.; Ouyang, Y.; Wen, Z.; Zheng, G.; Wan, T.; Sun, G. Silencing of miR-483-5p alleviates postmenopausal osteoporosis by targeting SATB2 and PI3K/AKT pathway. Aging 2021, 13, 6945–6956.
  59. Sandova, V.; Pavlasova, G.M.; Seda, V.; Cerna, K.A.; Sharma, S.; Palusova, V.; Brychtova, Y.; Pospisilova, S.; Fernandes, S.M.; Panovska, A.; et al. IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3Kδ inhibitor idelalisib. Haematologica 2021, 106, 2995–2999.
  60. Polivka, J., Jr.; Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol. Ther. 2014, 142, 164–175.
  61. Lu, C.H.; Chen, Y.A.; Ke, C.C.; Chiu, S.J.; Jeng, F.S.; Chen, C.C.; Hsieh, Y.J.; Yang, B.H.; Chang, C.W.; Wang, F.S.; et al. Multiplexed Molecular Imaging Strategy Integrated with RNA Sequencing in the Assessment of the Therapeutic Effect of Wharton’s Jelly Mesenchymal Stem Cell-Derived Extracellular Vesicles for Osteoporosis. Int. J. Nanomed. 2021, 16, 7813–7830.
  62. Zhang, X.; Wang, Y.; Zhao, H.; Han, X.; Zhao, T.; Qu, P.; Li, G.; Wang, W. Extracellular vesicle-encapsulated miR-22-3p from bone marrow mesenchymal stem cell promotes osteogenic differentiation via FTO inhibition. Stem Cell Res. Ther. 2020, 11, 227.
  63. Feng, X.; Teitelbaum, S.L. Osteoclasts: New Insights. Bone Res. 2013, 1, 11–26.
  64. Kim, B.J.; Koh, J.M. Coupling factors involved in preserving bone balance. Cell. Mol. Life Sci. CMLS 2019, 76, 1243–1253.
  65. Xu, R.; Shen, X.; Xie, H.; Zhang, H.; Liu, D.; Chen, X.; Fu, Y.; Zhang, P.; Yang, Y.; Cheng, J.; et al. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 2021, 11, 5491–5510.
  66. Chen, C.Y.; Rao, S.S.; Tan, Y.J.; Luo, M.J.; Hu, X.K.; Yin, H.; Huang, J.; Hu, Y.; Luo, Z.W.; Liu, Z.Z.; et al. Extracellular vesicles from human urine-derived stem cells prevent osteoporosis by transferring CTHRC1 and OPG. Bone Res. 2019, 7, 18.
  67. Matsumoto, T.; Endo, I. RANKL as a target for the treatment of osteoporosis. J. Bone Miner. Metab. 2021, 39, 91–105.
  68. Dempster, D.W.; Lambing, C.L.; Kostenuik, P.J.; Grauer, A. Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: A review of preclinical and clinical data. Clin. Ther. 2012, 34, 521–536.
  69. Ren, L.; Song, Z.J.; Cai, Q.W.; Chen, R.X.; Zou, Y.; Fu, Q.; Ma, Y.Y. Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. Biochem. Biophys. Res. Commun. 2019, 508, 138–144.
  70. Lee, K.S.; Lee, J.; Kim, H.K.; Yeom, S.H.; Woo, C.H.; Jung, Y.J.; Yun, Y.E.; Park, S.Y.; Han, J.; Kim, E.; et al. Extracellular vesicles from adipose tissue-derived stem cells alleviate osteoporosis through osteoprotegerin and miR-21-5p. J. Extracell. Vesicles 2021, 10, e12152.
  71. Xiao, F.; Zuo, B.; Tao, B.; Wang, C.; Li, Y.; Peng, J.; Shen, C.; Cui, Y.; Zhu, J.; Chen, X. Exosomes derived from cyclic mechanical stretch-exposed bone marrow mesenchymal stem cells inhibit RANKL-induced osteoclastogenesis through the NF-κB signaling pathway. Ann. Transl. Med. 2021, 9, 798.
  72. Ramasamy, S.K.; Kusumbe, A.P.; Schiller, M.; Zeuschner, D.; Bixel, M.G.; Milia, C.; Gamrekelashvili, J.; Limbourg, A.; Medvinsky, A.; Santoro, M.M.; et al. Blood flow controls bone vascular function and osteogenesis. Nat. Commun. 2016, 7, 13601.
  73. Kusumbe, A.P.; Ramasamy, S.K.; Adams, R.H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 2014, 507, 323–328.
  74. Song, C.; Cao, J.; Lei, Y.; Chi, H.; Kong, P.; Chen, G.; Yu, T.; Li, J.; Prajapati, R.K.; Xia, J.; et al. Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation. FASEB J. 2020, 34, 4798–4811.
  75. Anderson, J.D.; Johansson, H.J.; Graham, C.S.; Vesterlund, M.; Pham, M.T.; Bramlett, C.S.; Montgomery, E.N.; Mellema, M.S.; Bardini, R.L.; Contreras, Z.; et al. Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling. Stem Cells 2016, 34, 601–613.
  76. Qi, X.; Zhang, J.; Yuan, H.; Xu, Z.; Li, Q.; Niu, X.; Hu, B.; Wang, Y.; Li, X. Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone Defects through Enhanced Angiogenesis and Osteogenesis in Osteoporotic Rats. Int. J. Biol. Sci. 2016, 12, 836–849.
  77. Cui, Y.; Guo, Y.; Kong, L.; Shi, J.; Liu, P.; Li, R.; Geng, Y.; Gao, W.; Zhang, Z.; Fu, D. A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis. Bioact. Mater. 2022, 10, 207–221.
  78. Behera, J.; Kumar, A.; Voor, M.J.; Tyagi, N. Exosomal lncRNA-H19 promotes osteogenesis and angiogenesis through mediating Angpt1/Tie2-NO signaling in CBS-heterozygous mice. Theranostics 2021, 11, 7715–7734.
  79. Liu, H.; Li, D.; Zhang, Y.; Li, M. Inflammation, mesenchymal stem cells and bone regeneration. Histochem. Cell Biol. 2018, 149, 393–404.
  80. Srivastava, R.K.; Dar, H.Y.; Mishra, P.K. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Front. Immunol. 2018, 9, 657.
  81. Du, Y.M.; Zhuansun, Y.X.; Chen, R.; Lin, L.; Lin, Y.; Li, J.G. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp. Cell Res. 2018, 363, 114–120.
  82. Chen, W.; Huang, Y.; Han, J.; Yu, L.; Li, Y.; Lu, Z.; Li, H.; Liu, Z.; Shi, C.; Duan, F.; et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol. Res. 2016, 64, 831–840.
  83. Zhang, L.; Wang, Q.; Su, H.; Cheng, J. Exosomes from adipose derived mesenchymal stem cells alleviate diabetic osteoporosis in rats through suppressing NLRP3 inflammasome activation in osteoclasts. J. Biosci. Bioeng. 2021, 131, 671–678.
  84. Yang, C.; Lim, W.; Park, J.; Park, S.; You, S.; Song, G. Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells. Mol. Hum. Reprod. 2019, 25, 755–771.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cell & Tissue Engineering
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Yajing Yang
,
Lei Yuan
,
Hong Cao
,
Jianmin Guo
,
Xuchang Zhou
,
Zhipeng Zeng
View Times: 829
Revisions: 2 times (View History)
Update Date: 23 Dec 2022
Table of Contents
Academic Video Service
Feedback