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Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies

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ABSTRACT

Adult mesenchymal stem cells (MSCs) represent a subject of intense experimental and biomedical interest. Recently, trophic activities of MSCs have become the topic of a number of revealing studies that span both basic and clinical fields. In this review, we focus on recent investigations that have elucidated trophic mechanisms and shed light on MSC clinical efficacy relevant to musculoskeletal applications. Innate differences due to MSC sourcing may play a role in the clinical utility of isolated MSCs. Pain management, osteochondral, nerve, or blood vessel support by MSCs derived from both autologous and allogeneic sources have been examined. Recent mechanistic insights into the trophic activities of these cells point to ultimate regulation by nitric oxide, nuclear factor-kB, and indoleamine, among other signaling pathways. Classic growth factors and cytokines—such as VEGF, CNTF, GDNF, TGF-β, interleukins (IL-1β, IL-6, and IL-8), and C-C ligands (CCL-2, CCL-5, and CCL-23)—serve as paracrine control molecules secreted or packaged into extracellular vesicles, or exosomes, by MSCs. Recent studies have also implicated signaling by microRNAs contained in MSC-derived exosomes. The response of target cells is further regulated by their microenvironment, involving the extracellular matrix, which may be modified by MSC-produced matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs. Trophic activities of MSCs, either resident or introduced exogenously, are thus intricately controlled, and may be further fine-tuned via implant material modifications. MSCs are actively being investigated for the repair and regeneration of both osteochondral and other musculoskeletal tissues, such as tendon/ligament and meniscus. Future rational and effective MSC-based musculoskeletal therapies will benefit from better mechanistic understanding of MSC trophic activities, for example using analytical “-omics” profiling approaches.

No MeSH data available.


MSC trophic mechanisms depend on MSC interactions with and modification of the local environment. MSC trophic functions can be both achieved and altered through dynamic ECM–cytoskeletal interactions, cell–cell contacts, and soluble and transcription factor signaling. ECM extracellular matrix, miRNA microRNA, MMP matrix metalloproteinase, MSC mesenchymal stem cell, TIMP tissue inhibitor of metalloproteinase
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Fig1: MSC trophic mechanisms depend on MSC interactions with and modification of the local environment. MSC trophic functions can be both achieved and altered through dynamic ECM–cytoskeletal interactions, cell–cell contacts, and soluble and transcription factor signaling. ECM extracellular matrix, miRNA microRNA, MMP matrix metalloproteinase, MSC mesenchymal stem cell, TIMP tissue inhibitor of metalloproteinase

Mentions: Clues to the mechanisms of MSC trophic activities (Fig. 1) can also be found in the extensive work done in other fields, particularly exploration of the stem cell secretome in the cardiac field [58]. Identified factors include adrenomedullin, angiogenin, fibroblast growth factor-2 (FGF2), CXCL12, cistatin C, cysteine-rich angiogenic inducer 61 (Cyr61), Dickkopf-related proteins (Dkk), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), IL-1, IL-6, pigmented epithelium-derived factor (PEDF), placental growth factor (PLGF), SDF1, TSG6, VEGF, MMP-2, tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, secreted frizzled related protein-2 (SFRP-2), thrombospondin-1, and tenascin C [58]. Belying their osseous origin, CM of BM-MSC appears enriched in molecules typically secreted by or influencing osteoblasts, including decorin, osteoprotegerin, Dkk-3, receptor activator of nuclear factor-kB (RANK), osteopontin, and CCL5; inflammatory factors maximally produced by BM-MSCs include CCL2, TIMP-2, IL-6, IL-7, IL-3, MMP-7, chemokine (C-X-C) receptor-16 (CXCR16), and MMP-10. CCL2 and CCL7 produced by BM-MSCs appear to strongly influence nascent bone formation [59, 60]. Recent work also suggests that AD-MSC, BM-MSC, and dental pulp stem cell-secreted CXCL14 and CCL2 help to recruit CXCR4+ cells and chemokine (C-C) receptor-2+ (CCR2+) vessel-associated cells, without inducing proliferation [61]. Besides these influential but potentially short-lived proteins, some MSCs secrete EVs which may contain any number of influential molecules, protected from systemic degradation by virtue of their natural, membrane-bound packaging [62–65].Fig. 1


Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies
MSC trophic mechanisms depend on MSC interactions with and modification of the local environment. MSC trophic functions can be both achieved and altered through dynamic ECM–cytoskeletal interactions, cell–cell contacts, and soluble and transcription factor signaling. ECM extracellular matrix, miRNA microRNA, MMP matrix metalloproteinase, MSC mesenchymal stem cell, TIMP tissue inhibitor of metalloproteinase
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5016979&req=5

Fig1: MSC trophic mechanisms depend on MSC interactions with and modification of the local environment. MSC trophic functions can be both achieved and altered through dynamic ECM–cytoskeletal interactions, cell–cell contacts, and soluble and transcription factor signaling. ECM extracellular matrix, miRNA microRNA, MMP matrix metalloproteinase, MSC mesenchymal stem cell, TIMP tissue inhibitor of metalloproteinase
Mentions: Clues to the mechanisms of MSC trophic activities (Fig. 1) can also be found in the extensive work done in other fields, particularly exploration of the stem cell secretome in the cardiac field [58]. Identified factors include adrenomedullin, angiogenin, fibroblast growth factor-2 (FGF2), CXCL12, cistatin C, cysteine-rich angiogenic inducer 61 (Cyr61), Dickkopf-related proteins (Dkk), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), IL-1, IL-6, pigmented epithelium-derived factor (PEDF), placental growth factor (PLGF), SDF1, TSG6, VEGF, MMP-2, tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, secreted frizzled related protein-2 (SFRP-2), thrombospondin-1, and tenascin C [58]. Belying their osseous origin, CM of BM-MSC appears enriched in molecules typically secreted by or influencing osteoblasts, including decorin, osteoprotegerin, Dkk-3, receptor activator of nuclear factor-kB (RANK), osteopontin, and CCL5; inflammatory factors maximally produced by BM-MSCs include CCL2, TIMP-2, IL-6, IL-7, IL-3, MMP-7, chemokine (C-X-C) receptor-16 (CXCR16), and MMP-10. CCL2 and CCL7 produced by BM-MSCs appear to strongly influence nascent bone formation [59, 60]. Recent work also suggests that AD-MSC, BM-MSC, and dental pulp stem cell-secreted CXCL14 and CCL2 help to recruit CXCR4+ cells and chemokine (C-C) receptor-2+ (CCR2+) vessel-associated cells, without inducing proliferation [61]. Besides these influential but potentially short-lived proteins, some MSCs secrete EVs which may contain any number of influential molecules, protected from systemic degradation by virtue of their natural, membrane-bound packaging [62–65].Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Adult mesenchymal stem cells (MSCs) represent a subject of intense experimental and biomedical interest. Recently, trophic activities of MSCs have become the topic of a number of revealing studies that span both basic and clinical fields. In this review, we focus on recent investigations that have elucidated trophic mechanisms and shed light on MSC clinical efficacy relevant to musculoskeletal applications. Innate differences due to MSC sourcing may play a role in the clinical utility of isolated MSCs. Pain management, osteochondral, nerve, or blood vessel support by MSCs derived from both autologous and allogeneic sources have been examined. Recent mechanistic insights into the trophic activities of these cells point to ultimate regulation by nitric oxide, nuclear factor-kB, and indoleamine, among other signaling pathways. Classic growth factors and cytokines—such as VEGF, CNTF, GDNF, TGF-β, interleukins (IL-1β, IL-6, and IL-8), and C-C ligands (CCL-2, CCL-5, and CCL-23)—serve as paracrine control molecules secreted or packaged into extracellular vesicles, or exosomes, by MSCs. Recent studies have also implicated signaling by microRNAs contained in MSC-derived exosomes. The response of target cells is further regulated by their microenvironment, involving the extracellular matrix, which may be modified by MSC-produced matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs. Trophic activities of MSCs, either resident or introduced exogenously, are thus intricately controlled, and may be further fine-tuned via implant material modifications. MSCs are actively being investigated for the repair and regeneration of both osteochondral and other musculoskeletal tissues, such as tendon/ligament and meniscus. Future rational and effective MSC-based musculoskeletal therapies will benefit from better mechanistic understanding of MSC trophic activities, for example using analytical “-omics” profiling approaches.

No MeSH data available.