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

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.

Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes

“…A wide range of evidence indicates that paracrine effects of MSC are a central mechanism of cell therapy promoting tissue regeneration [29, 30]. In line with this view, we have previously shown that CM from ADMSC exhibits anti-inflammatory properties in OA chondrocytes [20].…”

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

“…Because the delivery of regenerative trophic factors to the site of injury is now being considered the primary mechanism of MSC‐mediated tissue repair (Fu et al, ; Hofer & Tuan, ), the levels of VEGF, SCF, and IL‐6 were quantified in cell culture supernatants on Days 1, 5, 8, and 12 (Figure a–c). VEGF is an angiogenic and pro‐regenerative growth factor (Arsic et al, ).…”

Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization

“…Concerning factors released by MSCs that could be involved in the acquisition of chemoresistance by tumor cells, several authors have identified CCL5, IL-6 and the C-X-C motif chemokine ligand 8 (CXCL8 or IL-8) [16][17][18]. This last cytokine has been implicated in a number of inflammatory diseases involving the chemo-attraction and activation of neutrophils.…”