Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

Table 3 Strategies to enhance stem cell transplantation therapy

Strategy	Method	Target	Effects	Molecular mechanisms	Ref.
Preconditioning	Short repeated ischemia/reperfusion	ESCs	Enhancing the tolerance of subsequent prolonged lethal ischemia	Promoting the expression of trophic factors, inducing the release and activation of PKC, PKB, or Akt, NF-κB and Src protein tyrosine kinases, and subsequently upregulating COX-2, iNOS, HO-1, Mn superoxide dismutase, aldose reductase, and antiapoptotic genes	[210-212]
	Hypoxia	MSCs	Promoting mesenchymal stem cell migration and survival	Increasing the expression of lncRNA-p21, HIF-1α, and CXCR4/7(both were chemokine SDF-1 receptors)	[213]
		CSCs	Promoting survival and cardiogenic differentiation	Inducing the activation of the HIF-1α/apelin/APJ axis	[214]
		NSCs	Promoting survival and neuroprotective properties, and facilitating functional recovery in vivo	Upregulating HIF1-α and HIF target genes such as EPO and VEGF and neurotrophic, and growth factors	[215]
	Hydrogen peroxide preconditioning	BMSCs	Improving the therapeutic potential for wound healing	Upregulating cyclin D1, SDF-1, and its receptors CXCR4/7 expression, and activating the PI3K/Akt/mTOR pathway, but inhibiting the expression of p16 and GSK-3β	[216]
	Nitric oxide donor preconditioning	hCSCs	Enhancing survival	Upregulating phosphorylation of NRF2, NFκB, STAT3, ERK, and AKT, as well as increasing the protein expression of HO-1 and COX2	[217]
	Heat shocking	MSCs	Promoting migration	Triggering the activation of ERK and PI3K/Akt signaling pathways via HSP90	[218]
Pretreatment	Oxytocin	MSCs	Antiapoptosis and cell protection	Increasing the expression of Akt and phospho-ERK1/2 proteins, rapid calcium mobilization, and upregulation of antiapoptotic and angiogenic genes including HSP27/32/70, TIMP-1/2/3, VEGF, thrombospondin, and matrix metalloproteinase-2	[219]
	Minocycline	NSCs	Increasing the capacity of migration, proliferation, and differentiation to improve neurological recovery	Increasing the expression of Nrf2	[220,221]
	Melatonin	MSCs	Inducing fewer fibrotic damage	Downregulating the levels of TNF-α, TGF-β, and α-SMA, and upregulating the expression of E-cadherin	[222]
	Extremely low-level lasers	MSCs	Enhancing the migration of MSCs; promoting the proliferation rate of SCs	Allowing the FAK and ERK1/2 pathways and increasing PDGF and HGF; inducing the up-regulation of mitochondrial ROS and NO	[223,224]
Genetic strategies	Overexpressing pro-survival factors	hNSCs	Improving short- and long-term survival	Overexpression of Bcl-2, Bcl-xl, Hif1a, or/and Akt1	[225]
	Genetic modification	MSCs	Potentiating MSC survival	Overexpression of ERBB4 and ILK	[226]
3D technology	Hydrogels mimicking	MSCs, ESCs, EPCs	Role in stem cell differentiation, changing matrix stiffness, mechanical stress and strain, nonlinear elastic, microenvironments and viscoelastic microenvironments	N/A	[227]
Co-transplantation	Co-transplantation of MSCs and HSCs	MSCs HSCs	Enhancing therapeutic effects	N/A	[228]

ESCs: Embryonic stem cells; NSCs: Neural stem cells; MSCs: Mesenchymal stem cells; HSCs: Hematopoietic stem cells; EPCs: Endothelial progenitor cells; hNSCs: Human neural stem cells; SCs: Stem cells; Hsp70/90: Heat shock protein 70/90; ERK: Extracellular regulated protein kinases; Nrf2: Nuclear factor erythroid 2; TNF: Tumor necrosis factor; TGF: Tumor growth factor; SMA: Smooth muscle actin; HGF: Hepatocyte growth factor; ROS: Reactive oxygen species; Bcl-2: B-cell lymphoma 2; ERBB4: Erb-b2 receptor tyrosine kinase 4; ILK: Integrin-linked kinase; SDF-1: Stromal-derived factor-1; EPO: Erythropoietin; VEGF: Vascular endothelial growth factor; TIMP: Tissue inhibitor of metalloproteinase; PDGF: Platelet-derived growth factor.