Table 2.
MenSCs and regenerative effects
| Organ/Disease | Animal model | Transplantation method | Reparative/Regenerative effect | Pathway/Paracrine molecules involved | References | |
|---|---|---|---|---|---|---|
| Myocardial infarction (MI) | MI | Rat model of myocardial infarction (MI) | Intracardial MenSC injection | Improve cardiac function. Minor trans-differentiation to cardiomyocytes | Secreted cytokines (PDGF, EGF, NO and TGF-β2. Activation of Akt/Stat3 pathway. Decrease apoptosis | (Hida et al., 2008; Jiang et al., 2013) |
| MI | Rat model of myocardial infarction (MI) | Intracardial MenSC exosomes injection | Enhance myocardial cell survival and microvessel density | Secreted exosomal miR-21 enhances cell survival through the PTEN/Akt pathway | (Wang et al., 2017) | |
| Liver | Acute liver failure | BALB/c mouse (CCl444 induction) | Intravenous MenSC injection | Liver regeneration. No study of molecules involved | (Fathi-Kazerooni et al., 2017) | |
| Liver fibrosis | BALB/c mouse (CCl4 induction) | Intravenous MenSC injection | Liver regeneration. Dicreased collagen deposition. | Secretion of paracrine cytokines: MCP-1, GRO, IL-6, HGF, OPG and IL-8 | (Chen et al., 2017b) | |
| Fulminant hepatic failure (FHF) | D-GalN/LPS-induced FHF mice | Intravenous MenSC exosomes injection | Reduced hepatocyte apoptosis, proliferation of liver macrophages and pro-inflammatory cytokines improving liver function | Potential role of exosome cytokines: ICAM-1, Ang2, Axl, ANG, IGFBP-6, OPG, IL-6 and IL-8 on the reduction of the number of liver MNCs and the amount of the active apoptotic protein caspase-3 in injured liver | (Chen et al., 2017a) | |
| Lung | Acute lung injury | C57BL6 mouse (LPS-injury) | Intravenous MenSC injection | Attenuate inflammation (decrease IL-1β and increase IL-10) increase microvascular permeability and tissue repair (increase PCNA and decrease caspase-3). No study of molecules involved | Potential molecules involved in PI3K/β-catenin cross-talked with the gsk3β/β-catenin | (Xiang et al., 2017) |
| Pulmonary fibrosis | C57BL6 mouse (bleomycin) | Intravenous MenSC injection | - Decrease collagen production and wet/dry lung weight - Anti-inflammatory effect: Lower TGF-β, IL-1β and TNF-α and incrased IL-10 in serum and lung | Potential antiapoptotic effect via suppression of Bax expression, while increasing the antiapoptotic gene Bcl-2 in lung cells and antifibrosis effect via up regulation of HGF and MMP-9 | (Zhao et al., 2018b) | |
| Critical limb ischemia | BALB/c mouse (surgery induced) | MenSC injection into the hindlimb muscle | Decreased muscle necrosis | Detection of paracrine secreted factors: IL-4, HIF-a, MMP-3 an MMP-10 | (Murphy et al., 2008) | |
| Skin wound repair | C57BL6 mouse (surgery induced injury) | Intradermal injection of MenSC | Improve wound closure and vascularization | Increase MenSC expression of ANGPT1, PDGFA; PDGFB; MMP3; ELN; and MMP10, IL-8 and VEGF | (Cuenca et al., 2018) | |
| Diabetes mellitus | C57BL/6 mouse model of diabetes (STZ induced) | Intradermal injection of MenSC exosomes | Faster re-epithelialization and less scar formation | Secreted exosomes enhance neoangiogenesis through VEGFA upregulation and Re-epithelialization activation of the NF-κB signaling pathway | (Dalirfardouei et al., 2019) | |
| BALB/c mouse type 1 diabetes (STZ induced) | Intravenous MenSC injection | Reverse hyperglycemia and weight loss, prolong lifespan, and increase insulin production | β- cell regeneration by facilitating endogenous progenitor cell differentiation (increase of Ngn3+ progenitors) | (Wu et al., 2014) | ||
| Rat model of diabetes (STZ induced) | Intravenous injection of MenSC exosomes | Enhance the regeneration β- cell number and increased insulin production | Potential induction of islet regeneration through pancreatic and duodenal homeobox 1 (Pdx-1) pathway | (Mahdipour et al., 2019) | ||
| Neural related | OGD stroke | Rat oxygen glucose deprivation (OGD) stroke model | Intracerebral and intravenous MenSC injection | Decreased neuronal cell death and improved motor symptoms | MenSC secretion of BDNF, VEGF and NT-3 | (Borlongan et al., 2010) |
| SCI | Rat SC hemisection model | MenSC injection into spinal cord injured site | Improved the hindlimb motor function. Increase number of neurons, axon regeneration. Decrease inflammatory factors TNF-α and IL-1β | Regeneration mediated via the upregulation of BDNF in injured area | (Wu et al., 2018) | |
| Alzheimer's disease | APP/PS1 transgenic mice | Intracerebral MenSC injection | Improved the spatial learning and memory decrease number amyloid plaques and reduced tau hyperphosphorylation | Potential role of MenSC inducing the conversion of activated microglia to an alternative phenotype that secrete Aβ-degrading enzymes, including insulin-degrading enzyme (IDE) and neprilysin (NEP) | (Zhao et al., 2018a) | |
| Oral squamous cell carcinoma | Hamster buccal pouch carcinoma (DMBA induced) | MenSCs exosome intratumoral injection | Decrease tumor growth and a loss of tumor vasculature | Induction of apoptosis in endothelial cells and of their secretion of VEGF to increase angiogenesis | (Rosenberger et al., 2019) | |
| Premature ovarian failure (POF) | Rat busulfan model | Intravenous MenSC injection | Increase the number of follicles and restored the ovarian hormones estrogen and progesterone in plasma | MenSC localize in granulosa cells layer of immature follicles. Potential effect on follicle maturation. | (Manshadi et al., 2019) | |
| C57BL/6 mouse model (CTX induced) | Intravenous MenSC injection | Regulation of normal follicle development and estrous cycle and restoration of ovarian hormones (FSH, E2 and AMH) increase number of live births | Potential activation of ovarian transcriptional expression in ECM-dependent FAK/AKT signaling pathway | (Feng et al., 2019) | ||
| Endometrial injury and intrauterine adhesion (IUA) | ICR mouse (electrocoagulation) | Intravenous MenSC injection | Endometrium restoration with increased endometrial thickness and microvessel density. Increases embryo number | Secreted molecules (not identified) with potential activation of AKT and ERK pathways that induce the overexpression of eNOS, VEGFA, VEGFR1, VEGFR2 and TIE2 in endothelial cells (pro-angiogenic) | (Zhang et al., 2016) | |
| Rat IUA (mechanical injured) | Intravenous MenSC injection | Improved endometrial proliferation, angiogenesis, and morphology recovery and decreased collagen fibrosis and inflammation in the uterus | Detection of secretory protein IGF-1, SDF-1, and TSP-1 in the uterus. Potential involvement of Hippo signaling pathway (CTGF, Wnt5a, and Gdf5) | (Zhang et al., 2019) | ||
Summary of regenerative effects of menstrual blood-derived stromal/stem cells (MenSCs).