Table 1.
Biological effect of MSC secretome-derived products on disease models.
| MSC source | Paracrine factors | Biological effect | Ref. |
|---|---|---|---|
| Skin wounds and radiation | |||
| Human adipose tissue | Supernatant of cell lysate | (i) Faster wound closure when applied topically on cutaneous wound (ii) Upregulation of dermal fibroblast proliferation, migration, and ECM production |
[25] |
| Human adipose tissue | Hypoxic conditioned medium | (i) Protected epithelial, endothelial, and myoepithelial cells from radiation damage and tissue remodelling | [92] |
| Adipose tissue | Exosomes | (i) Stimulated fibroblast migration, proliferation, and collagen synthesis (ii) Recruited to soft tissue wound in mouse skin incision model and accelerated cutaneous wound healing |
[137] |
| Human and murine bone marrow | Exosomes and microvesicles | (i) Mitigated radiation injury to marrow stem cells (ii) Restoration of marrow stem cell engraftment and partial recovery of peripheral blood counts postirradiation |
[41] |
| Human amniotic epithelial cells | Exosomes | (i) Promoted migration and proliferation of fibroblasts (ii) Deposition of ECM partly abolished (iii) In rat model, improved skin wound healing with well-organized collagen fibers |
[138] |
| Human umbilical cord blood | Exosomes | (i) Promoted cell migration and collagen synthesis of human dermal fibroblasts (ii) Increased expressions of collagen I and elastin 3 days posttreatment on human skin |
[139] |
|
| |||
| Bone and cartilage | |||
| Human fetal MSCs | Conditioned medium | (i) Increased expression of ALP and osteogenic marker genes and increased calcium deposits in rat BM-MSCs (ii) Improved bone consolidation in a rat osteogenesis model |
[26] |
| Human synovial membrane | Exosomes | (i) Enhance proliferation and antiapoptotic abilities of bone marrow-derived stromal cells (ii) Prevented GC-induced trabecular bone loss, bone marrow necrosis, and fatty cells accumulation in rat model |
[140] |
| Human embryo | Exosomes | (i) Enhanced gross appearance and histological scores of osteochondral defects in adult rats with complete restoration of cartilage and subchondral bone | [141] |
| Human bone marrow | Exosomes compared to exosome-free conditioned medium | (i) Exosomes, but not exosome-free conditioned medium, rescued retardation of fracture healing in CD9−/− mice | [31] |
| Human iPS-MSCs | Exosomes | (i) In a rat osteonecrosis model, exosomes prevented bone loss and increased microvessel density (ii) Enhanced proliferation, migration, and tube-forming capacities of endothelial cells in vitro |
[142] |
| Human bone marrow | Exosomes, miR-21 | (i) Suppressed TNF-α-induced nucleus pulposus cell apoptosis | [46] |
|
| |||
| Kidneys | |||
| SD rat bone marrow | Conditioned media compared to MSCs | (i) In an acute kidney injury model, MSCs and their CM equally ameliorated kidney function deterioration, Kim-1 shedding in urine, renal tissue damage, and tubular cell apoptosis (ii) Both reduced interstitial fibrosis |
[27] |
| Bone marrow | Conditioned medium, MSCs, and microvesicles | (i) Ameliorated induced acute kidney injury in rats with little differences in effectiveness between CM, microvesicles, and MSCs | [143] |
|
| |||
| Diabetes mellitus | |||
| Murine bone marrow | miR-106b-5p, miR-222-3p | (i) Promoted postinjury β-cell proliferation (ii) Improved hyperglycemia in STZ-treated mice |
[47] |
| Human adipose tissue | Conditioned media compared to MSCs | (i) Reversed mechanical, thermal allodynia, and thermal hyperalgesia (ii) Restored correct pro/anti-inflammatory cytokine balance and prevented skin innervation loss (iii) Reestablished Th1/Th2 balance in spleens of STZ-treated mice (iv) Recovered kidney morphology |
[144] |
| Human bone marrow | Extracellular vesicles | (i) Prevented onset of T1DM and experimental autoimmune uveoretinitis in a murine model (ii) Inhibited activation of antigen-presenting cells and suppressed development of Th1 and Th17 cells |
[145] |
|
| |||
| Cardiovascular system | |||
| Human embryonic MSCs | Exosomes | (i) Reduced infarct size in a mouse model of myocardial ischemia/reperfusion injury | [39] |
| SD rat bone marrow | Exosomes compared to MSCs | (i) Exosomes reduced inflammation, inhibited fibrosis, and improved cardiac function in rat myocardial infarction model (significantly superior to MSCs) (ii) Exosomes stimulated cardiomyocyte H9C2 cell proliferation, inhibited apoptosis, and inhibited fibroblast differentiation to myofibroblast |
[18] |
| SD rat bone marrow overexpressing Akt | Hypoxic conditioned medium | (i) Suppressed hypoxia-induced apoptosis and triggered contraction of adult rat cardiomyocytes (ii) Upregulation of VEGF, FGF-2, HGF, IGF-1, and TB4 in Akt-MSCs |
[146] |
| Human bone marrow | Conditioned medium—products >1000 kDa (100–220 nm) | (i) Cardioprotection in a mouse model of ischemia and reperfusion injury with a 60% reduction in infarct size (ii) Reduced myocardial nuclear oxidative stress (iii) Reduced TGF-β signalling and apoptosis (iv) Improved systolic and diastolic cardiac performance |
[38] |
| huES9.E1 | Exosomes | (i) Alleviated features of reperfusion injury (ii) Preservation of left ventricular geometry and contractile performance (iii) Increased levels of ATP and NADH and decreased oxidative stress (iv) Reduced local and systemic inflammation (v) Reduced infarct size by 45% |
[34] |
| Murine bone marrow | Exosomes enriched in miR-22 from ischemic preconditioned MSCs | (i) Reduced cardiac fibrosis in a myocardial infarction mouse model (ii) Mobilized to cardiomyocytes where they reduced apoptosis due to ischemia |
[91] |
| Human umbilical cord | Exosomes | (i) Improved cardiac systolic function and reduced cardiac fibrosis after litigation of LAD coronary artery in a rat model (ii) Protected myocardial cells from apoptosis and promoted tube formation |
[147] |
| SD rat bone marrow | Exosomes from GATA-4-overexpressing MSCs, miR-19a | (i) Restored cardiac contractile function and reduced infarct size following ligation of coronary artery in rat heart (ii) Increased cardiomyocyte survival and preserved mitochondrial membrane potential |
[148] |
| Murine bone marrow | Extracellular vesicles, miR-210 | (i) Improved angiogenesis and exerted a therapeutic effect on myocardial infarction in a mouse model (ii) miR-210 necessary for proangiogenic effect |
[45] |
| SD rat bone marrow | Exosomes | (i) Enhanced tube formation of human umbilical vein endothelial cells (ii) Impaired T cell function by inhibiting proliferation in vitro (iii) Reduced infarct size, preserved cardiac systolic and diastolic performance, and enhanced density of new capillaries in a rat myocardial infarction model |
[149] |
| SD rat bone marrow | Exosomes | (i) Reduced H2O2-induced ROS production and cell apoptosis of rat H9C2 cardiomyocytes | [150] |
| Human bone marrow | Exosomes from ischemic MSC culture conditions | (i) Induced angiogenesis via NFκB pathway in HUVECs | [88] |
| Human Wharton jelly | Microvesicles | (i) Improved survival rate and renal function in renal ischemia-reperfusion injury after cardiac death (ii) Decreased number of CD68+ macrophages in kidney (iii) Decreased protein levels of α-SMA and TGF-β1 and increased HGF levels |
[151] |
| Murine bone marrow | Extracellular vesicles | (i) Increased blood reperfusion and formation of new blood vessels in a hindlimb ischemia model | [134] |
|
| |||
| Cancer | |||
| Human embryonic kidney cell line 293 | GE11-positive exosomes containing miR-let-7a | (i) Suppressed tumour growth and development in tumour-bearing mice (ii) Delivered miRNA to EGFR-expressing xenograft breast cancer tissue |
[152] |
|
| |||
| Muscle injury | |||
| Human bone marrow | Conditioned media compared to exosomes | (i) Promoted myogenesis and angiogenesis in vitro (ii) Exosomes promoted muscle regeneration in a mouse muscle injury model |
[30] |
| Human adipose tissue | Extracellular vesicles | (i) Modulated anti-inflammatory effects inducing macrophage polarization (ii) Mitigated inflammatory milieu within injured tissues in CTX injury of mouse TA muscle (iii) Accelerated muscle regeneration process |
[89] |
|
| |||
| Immunomodulatory | |||
| Human umbilical cord blood | Microvesicles | (i) Decreased chemotactic index of CD14+ cells (enhanced immunomodulatory effect) | [83] |
| Human bone marrow | Conditioned medium, PGE2 | (i) CM from spheroids inhibited LPS-stimulated macrophages from secreting proinflammatory cytokines and increased their production of anti-inflammatory cytokines | [28] |
|
| |||
| CNS | |||
| Human bone marrow | Exosomes | (i) Promoted survival of retinal ganglion cells (RGCs) and regeneration of their axons (ii) Partially prevented RGC axonal loss and dysfunction |
[153] |
| Human bone marrow | Exosomes from hypoxic MSCs | (i) Intravitreal exosome treatment in a oxygen-induced retinopathy murine model partially preserved retinal vascular flow in vivo and reduced retina thinning | [154] |
| Bone marrow | Exosomes | (i) In T2DM rats, stroke treatment 3 days poststroke improved functional outcome and reduced blood brain barrier leakage and haemorrhage (ii) Increased axon and myelin density and oligodendrocyte and oligodendrocyte progenitor cell number (iii) Increased expression of ABCA1 and IGFR1 |
[155] |
| Human adipose tissue | Conditioned medium | (i) Protected SH-SY5Y neuron-like cells against H2O2-induced neurotoxicity (ii) Promoted recovery of normal axonal morphology, electrophysiological features, and cell viability |
[156] |
| SD rat bone marrow | Extracellular vesicles | (i) Promoted functional recovery and nerve regeneration of crush-injured sciatic nerves in rats | [157] |
| Wistar rat bone marrow | Conditioned medium | (i) Enhanced motor functional recovery, increased spared spinal cord tissue, enhanced GAP-43 expression, and attenuated inflammation after spinal cord injury in a rat model | [158] |
|
| |||
| Pulmonary | |||
| Bone marrow | Exosomes | (i) Reduced levels of white blood cells and neutrophils to bronchoalveolar lavage fluid in endotoxin-injured mice | [94] |
| Human bone marrow | Microvesicles | (i) Reduced symptoms of idiopathic pulmonary fibrosis such as reduced collagen deposition and inflammation in mouse fibrosis model | [159] |
| Human Wharton jelly, bone marrow | Exosomes | (i) Ameliorated alveolar simplification, fibrosis, and pulmonary vascular remodelling in a hyperoxia-exposed mouse model (ii) Suppressed proinflammatory macrophage M1 state and augmented anti-inflammatory M2 state |
[160] |
| SD rat bone marrow | Microvesicles | (i) Alleviated PAH in a rat model by regulating the angiotensin system (ii) Relieved pulmonary artery pressure, pulmonary vessel wall thickness and lumen area, right ventricular hypertrophy, inflammation, and collagen fiber volume |
[161] |
|
| |||
| Liver | |||
| Human umbilical cord | Exosomes | (i) Reduced surface fibrous capsules and alleviated hepatic inflammation and collagen deposition in a mouse model of CCl4-induced liver fibrosis | [162] |