. 2021 Jun 24;18(3):933–951. doi: 10.1007/s12015-021-10185-z

Table 4.

Mechanisms of MSC and MSC-derived exosomes involved in regenerative medicine abbreviation

disorders	MSC related mechanisms	MSC derived exosome related mechanisms
bone regeneration and Osteoporosis improvement	1. increased monocyte differentiation to M2 macrophage 2. decreased production of proinflammatory cytokines such as IL-6, IL-1, and TNF-a 3. Migration to bone injury site by specific chemokine receptors 4. Stimulation of osteoblastic differentiation 5. Increase angiogenesis at the site of injury 6. Creating a regenerating microenvironment exosomes	1. carry osteogenic related mi-RNAs such as miR-196a, miR-27a, and miR-206 2. increasing the recruitment of MSCs to the fracture site by stimulation of MCP-1, MCP-3, and SDF-1 production 3. increasing mineral deposition in osteoblasts 4. increasing angiogenesis by stimulating VGEF expression and suppress SPRED1 suppression 5. increasing the differentiation of hMSCs into osteoblasts by stimulating COL1, ALP expression 6. increase MSC osteoblastic differentiation by activating the BMP-2/Smad1/RUNX2 signaling pathway 7. increasing survival, proliferation, and differentiation MAPK signaling pathway in osteoblasts 8. inhibit apoptosis in BM-MSCs by miR-1263 / Mob1 / Hippo signaling pathway
cartilage repair	1. producing ECM components such as collagen, fibronectin, proteoglycans, and glycosaminoglycans 2. prevent chondrocyte apoptosis 3. modulate the immune microenvironment of the injury site	1. create a regenerative environment for tissue repair 2. stimulation of cell proliferation through adenosine catalysis, enzymes ERK1 / 2 and AKT 3. increased extracellular matrix synthesis 4. increase chondrocytes mitochondrial function by transferring inactive glycolytic enzymes to them 5. Inhibition the function of NF-kB transcription factor 6. transmit anti-inflammatory factors
IDD	1. stimulate proliferation in the NPCs 2. differentiate to NP-like cells 3. prevents abnormal deposition and aggregation of type 1 collagen by MMP12 and HSP47 production 4. increase angiogenesis and pain-inducing nerve fibers growth 5. exert immunomodulatory effects on NP cells	1. modulate the inflammatory environment 2. increase proliferation in NPCs 3. increase ECM production in NPCs 4. decrease NPCs apoptosis via suppression PTEN expression (by mir-21 transmission) 5. reducing the stress of the NPC 6. reduce AGEs related endoplasmic reticulum stress in NPCs
tendon	1. immunomodulatory effect 2. differentiate to tenocytes 3. stimulate proliferation and differentiation in CD146 + progenitor cells by the FAK/ERK1/2 signaling pathway	1. increase the tendon stem cell migration 2. increase the anti-inflammatory macrophages migration to the site of injury 3. increase the expression of COL1a1 and COL3a1

disorders

MSC related mechanisms

MSC derived exosome related mechanisms

bone regeneration and Osteoporosis improvement

1. increased monocyte differentiation to M2 macrophage

2. decreased production of proinflammatory cytokines such as IL-6, IL-1, and TNF-a

3. Migration to bone injury site by specific chemokine receptors

4. Stimulation of osteoblastic differentiation

5. Increase angiogenesis at the site of injury

6. Creating a regenerating microenvironment

exosomes

1. carry osteogenic related mi-RNAs such as miR-196a, miR-27a, and miR-206

2. increasing the recruitment of MSCs to the fracture site by stimulation of MCP-1, MCP-3, and SDF-1 production

3. increasing mineral deposition in osteoblasts

4. increasing angiogenesis by stimulating VGEF expression and suppress SPRED1 suppression

5. increasing the differentiation of hMSCs into osteoblasts by stimulating COL1, ALP expression

6. increase MSC osteoblastic differentiation by activating the BMP-2/Smad1/RUNX2 signaling pathway

7. increasing survival, proliferation, and differentiation MAPK signaling pathway in osteoblasts

8. inhibit apoptosis in BM-MSCs by miR-1263 / Mob1 / Hippo signaling pathway

cartilage repair

1. producing ECM components such as collagen, fibronectin, proteoglycans, and glycosaminoglycans

2. prevent chondrocyte apoptosis

3. modulate the immune microenvironment of the injury site

1. create a regenerative environment for tissue repair

2. stimulation of cell proliferation through adenosine catalysis, enzymes ERK1 / 2 and AKT

3. increased extracellular matrix synthesis

4. increase chondrocytes mitochondrial function by transferring inactive glycolytic enzymes to them

5. Inhibition the function of NF-kB transcription factor

6. transmit anti-inflammatory factors

IDD

1. stimulate proliferation in the NPCs

2. differentiate to NP-like cells

3. prevents abnormal deposition and aggregation of type 1 collagen by MMP12 and HSP47 production

4. increase angiogenesis and pain-inducing nerve fibers growth

5. exert immunomodulatory effects on NP cells

1. modulate the inflammatory environment

2. increase proliferation in NPCs

3. increase ECM production in NPCs

4. decrease NPCs apoptosis via suppression PTEN expression (by mir-21 transmission)

5. reducing the stress of the NPC

6. reduce AGEs related endoplasmic reticulum stress in NPCs

tendon

1. immunomodulatory effect

2. differentiate to tenocytes

3. stimulate proliferation and differentiation

in CD146 + progenitor cells by the FAK/ERK1/2 signaling pathway

1. increase the tendon stem cell migration

2. increase the anti-inflammatory macrophages migration to the site of injury

3. increase the expression of COL1a1 and COL3a1

ECM extracellular matrix, TNF-a tumor necrosis factor alpha, NF-kB Nuclear factor kappa-B, IL interlukine, MCP monocyte chemotactic protein, SDF Stromal cell-derived factor, RUNX2 Runt-related transcription factor 2, BMP bone morphogenic protein