Table 1 Mechanism of MSCs resistance to apoptosis.

From: The dual role of mesenchymal stem cells in apoptosis regulation

Pathways	Molecules	Mechanisms	Refs
Mitochondrial pathway	IL-6	Via the activation of the JAK-STAT3-Ref-1 and JAK-Stat3-Bcl-2/Bax-Caspase-3 pathways; Upregulate the mRNA expression of Cyclin D and Bcl-xl	[28, 37]
	PGE2	Via ERK1/2 and GSK3beta phosphorylation to increase Bcl-2 and decrease Bax expression	[29]
	TGF-β	Through TGF-β/Bax singling pathway	[30]
	miR-29a-3p	Regulate Bcl-2 and Bcl-xl genes	[31]
	miR-125b-5p	Repress the protein expression of p53, leading to the modulation of Bcl-2 and Bax to inhibit apoptosis	[32]
	miR-93	Through targeting the HDAC4/Bcl-2 axis	[33]
	miR-150-5p	Via targeting Bax	[34]
	lncRNA-UCA1	Target miR-873 via sponging, reducing the latter’s suppressive effects on its target XIAP, and this translated into AMPK phosphorylation and increased level of the antiapoptotic protein Bcl-2	[35]
		Enhance translocation of Bcl-2 to the nucleus	[36]
	CXCL12	Reduce caspase-3 activation and modulate the expression of the antiapoptotic protein Bcl-xl	[38]
		Upregulate p-AKT and p-Bad by PI3K-AKT-Bad pathway	[39]
Death receptor pathway		Suppress the protein expression levels of macrophage-related factors inducible nitric oxide synthase and TNF-α	[40]
	miR-21-5p	Modulate Fas-L expression	[41]
	miR-17	Regulate BRD4-mediated EZH2/TRAIL axis to essentially inhibit LPS-induced macrophages inflammation and apoptosis	[42]
		Via TLR3-regualted MAPK and NF-κB signaling pathway	[43]
Endoplasmic reticulum pathway	HGF	Via a microenvironment-dependent paracrine HGF/c-Met signaling mechanism to suppress ERS and its downstream pro-inflammatory and pro-apoptotic consequences	[44]
	TNF-inducible gene 6 protein	Suppress ERS-induced apoptosis and NF-κB activity	[45]
	miR-21	By alleviating ERS and inhibiting p38 MAPK	[46]
		By improving Myc expression through both stromal cell-derived factor 1 signal and contact effect	[47]
Upstream regulatory pathways	miR-29b-3p	Activate the PI3K/AKT pathway by carrying miR-29b-3p into neurons and silencing PTEN, thus reducing neuronal apoptosis	[49]
	miR-223	Inhibit the apoptosis of neurons in vitro by targeting PTEN, thus activating the PI3K/Akt pathway	[50]
	miR-144	Inhibit cell apoptotic injury in hypoxic conditions by delivering miR-144 to cells, where it targets the PTEN/AKT pathway	[51]
	miR-486-5p	By suppressing PTEN expression, activating the PI3K/AKT signaling pathway, and subsequently inhibiting the apoptosis of injured cardiomyocytes	[52]
	lncRNA-KLF3-AS1	Inhibit autophagy and apoptosis of IL-1beta-treated chondrocyte through PI3K/Akt/mTOR signaling pathway	[53]
	miR-132-3p	Downregulate the target protein RASA1, while upregulate the expression of Ras and the downstream PI3K phosphorylation	[54]
		Involve NRG-1/HER2, MAPK, PI3K/AKT, p-JNK/JNK, and p-STAT/STAT signaling pathways	[162]
		Involve G-CSF/PI3K/AKT pathway	[163]
		By inhibiting apoptosis of skin cells and promoting their proliferation through activating PI3K/AKT signaling pathway	[164]
	miR-369-3p	Downregulate the expression of YAF2, inhibit the stability of PDCD5/p53, and reduce the apoptosis of ovarian granulosa cells	[55]
	miR-644-5p	Inhibit the apoptosis of ovarian granulosa cell by targeting p53	[56]
	miR-125b-5p	Suppress the expression of the pro-apoptotic genes p53 and BAK1 in cardiomyocytes	[57]
	miR-455-3p	Target the MEKK1-MKK4-JNK signaling pathway	[58]
	miR-19a	Target SOX6, activate AKT, and inhibit JNK3/caspase-3 activation	[59]
		By inhibiting p38/MAPK pathway	[60,61,62]
Others		By transferring mitochondria	[63, 64]
		Increase the mitochondrial membrane potential and alleviate compression-induced mitochondrial damage to alleviate compression-mediated nucleus pulposus cell apoptosis	[65]
		Retard mitochondria damage and cell apoptosis by an AMPK-PGC1-alpha axis	[66]
		Promote mitophagy and inhibit apoptosis and pyroptosis of renal tubular epithelial cells in kidney tissues by upregulating SIRT1/Parkin	[67]
		By reduce mitochondrial reactive oxygen species overproduction, decrease the accumulation of mitochondrial fragmentation, restore ATP generation and upregulate mitophagy	[68]
	miR-486	Reduce Smad1 expression by target regulating Smad1 whose reduction could inhibit mTOR activation, leading to the increase of autophagy and the reduction of podocyte apoptosis	[69]
		Through regulating Notch2/mTOR/autophagy signaling	[70]
	miR-217	Target EZH2, and EZH2 bound to the FOXO3 promoter and consequently downregulate its expression, which restrain NPC apoptosis and ECM degradation by stimulating cell autophagy	[71]
	ALKBH5	ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis	[72]
		Reduce pyroptosis in the injured liver and promote the expression of those factors related to liver regeneration, while they can inhibit the NF-κB pathway and activate the wnt/beta-catenin pathway	[73]
		Increase FOXO3a expression to enhance mitophagy, therefore protecting microglia from I/R-induced pyroptosis and alleviating subsequent neuronal injury	[74]
	miR-539-5p	Suppresses pyroptosis through NLRP3/caspase-1 signal	[75]
	circ-HIPK3	By regulate miR-421, resulting in increased expression of FOXO3a, leading to inhibition of pyroptosis and release of IL-1beta and IL-18	[76]
	miR-223-3p	Restrict cardiac inflammation, pyroptosis, and dysfunction by disrupting FOXO3/NLRP3 axis	[77]
	miR-26a-5p	Degrade METTL14 and thus decrease NLRP3	[78]
	circ-003564	Attenuate inflammasome-related pyroptosis via delivering circ-003564	[79]

MSCs mesenchymal stem cells, IL Lnterleukin, JAK Janus kinase, STAT signal transducer and activator of transcription, Ref-1 Redoxfactor-1, Bcl-2 B-cell lymphoma-2, PGE2 prostaglandin E2, ERK extracellular regulated protein kinases, GSK3β glycogen synthase kinase 3, TGF-β transforming growth factor-beta, HDAC histone deacetylase, miR micro RNA, XIAP X-linked inhibitor of apoptosis protein, AMPK Adenosine 5′-monophosphate-activated protein kinase, CXCL12 C-X-C motif chemokine 12, PI3K phosphatidylinositol 3-kinase, TNF-α Tumor necrosis factor-alpha, Fas-L Fas ligand, BRD4 bromodomain-containing protein 4, EZH2 enhancer of zeste homolog 2, TRAIL TNF-related apoptosis inducing ligand, LPS lipopolysaccharide, TLR3 Toll-like receptor 3, MAPK mitogen-activated protein kinase, HGF hepatocyte growth factor, ERS endoplasmic reticulum stress, PTEN phosphatase and tensin homolog, RASA1 Ras GTPase activating protein 1, NRG-1 neuregulin-1, HER2 human epidermal growth factor receptor-2, G-CSF granulocyte colony-stimulating factor, YAF2 YY1 associated factor 2, PDCD5 programmed cell death 5, BAK1 Bcl-2 antagonist/killer 1, MEKK1 MAPK kinase 1, MKK4 MAPK kinase 4, JNK c-Jun N-terminal kinase, SOX6 SRY-box transcription factor 6, PGC1 peroxisome proliferator-activated receptor gamma coactivator 1, SIRT1 Sirtuin 1, EZH2 enhancer of zeste homolog 2, FOXO3 forkhead box O3, NPC nucleus pulposus cells, ECM: extracellular matrix, ALKBH5 ALKB homolog 5, FIP200 FAK-family interacting protein of 200 kDa, NLRP3 NOD-like receptor thermal protein domain associated protein 3, METTL14 methyltransferase-like protein 14.

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Table 1 Mechanism of MSCs resistance to apoptosis.

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