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

Table 2 Molecular mechanisms and therapeutic targets of programmed cell deaths in stem cells

PCDs	SCs	Molecular pathways of PCDs	Therapeutic target(s)	Therapeutic effects	Ref.
Apoptosis	hESCs	Mitochondrial priming and p53 signaling pathway	Bcl-2	Preventing damaged cells from compromising the genomic integrity of the population	[119]
	HSCs	ASPP1 stimulated p53 signaling pathway	ASPP1, RUNX1	Preventing hematological malignancies	[120]
	ISCs	ARTS/XIAP/caspase 9 axis	XIAP	Controlling ISC numbers and preventing the propagation of abnormal progeny	[121]
	MSCs	p38 MAPK regulated early apoptosis while JNK regulated late apoptosis	p38	Protecting MSCs from oxidative stress damage	[38]
	NSCs	p38 MAPK signaling	TNF-α, p38	Impairing cell viability, decreasing therapeutic effects	[122]
Autophagy	iPSCs	AMPK/mTOR/ULK1 complex/PI3K complex/conjugation cascade complexes with LC3 and Atg9 during macroautophagy;KFERQ domain/Hsc 70/LAMP2A during CMA	LC3	Removing unnecessary or dysfunctional components	[123]
	HSCs	type III PI3K mammalian Atg6/PIP3/(Atg12-Atg5-Atg16) or (Atg4/LC3-I/Atg7/Atg3/LC3-II/PE) axis	LC3-II	Recycling cytoplasmic constituents and restoring metabolic homeostasis, and maintaining cells survival under harsh conditions	[124]
	NSCs	PI3K-AKT-mTOR/ULK1/the class III PI3-kinase-Beclin1 complex/PI3/PI3P/ the complex of Atg12–Atg5–Atg16L1/LC3-I/LC3-II axis	mTOR	Being involved in modulation of the embryonic neurogenesis as well as the injury repair of adult brain	[125]
	MSCs	PI3K/AKT/mTOR/ULK1/the class III PI3-kinase-Beclin1 complex/PI3/PI3P/the complex of Atg12–Atg5–Atg16L1/LC3-I/LC3-II axis	AKT, mTOR	Eliminating damaged organelles and biomacromolecules to maintain cellular homeostasis	[126,127]
	ESCs	AMPK/ mTORC1/ULK1 axis	Atg5, Atg12	Maintaining the undifferentiated state of ESCs in vitro	[128]
Necroptosis	ISCs	ZBP1/RIP3/MLKL axis	ZBP1	Disrupting homeostasis of the epithelial barrier and promoting bowel inflammation	[35,129]
	SSCs	RIP1 signaling pathway	RIP1	Using Nec-1 to target RIP1 for reducing both necroptosis and apoptosis, which benefits for recovery rate and proliferation potential	[130]
	NPSCs	RIPK1/RIPK3/MLKL axis	HSP90	Protecting SCs from PCD via alleviating mitochondrial dysfunction (mitochondrial membrane potential loss and ATP depletion) and oxidative stress (production of mitochondrial ROS), cellular total ROS and MDA, and downregulation of superoxide dismutase	[131]
Pyroptosis	MSCs	Exosome/circHIPK3/ FOXO3a axis	circHIPK3	Preventing pyroptosis and repairing ischemic muscle injury through a novel exosome	[132]
	ESCs	Caspase-1 signaling pathway	N/A	Embryonic stem cell-derived exosomes inhibit doxorubicin-induced pyroptosis	[133]
Ferroptosis	NPCs and IPSCs	Ferritin/ROS/lipid peroxidation axis	NCOA4, p53	Decreasing stem cells and triggering neuronal death	[134]

ISCs: Intestinal stem cells; iPCs: Induced pluripotent stem cells; HSCs: Hematopoietic stem cells; ESCs: Embryonic stem cells; NSCs: Neural stem cells; MSCs: Mesenchymal stem cells; EPCs: Endothelial progenitor cells; CPCs: Cardiac progenitor cells; IPSC: Pluripotent stem cells; ZBP1: Z-DNA-binding protein 1; RIP3: Receptor-interacting serine/threonine kinase 3; MLKL: Mixed lineage kinase domain like protein; PUMA: p53 upregulated modulator of apoptosis; NOXA: Known as PMAIP1, phorbol-12-myristate-13-acetate-induced protein 1; Bax: Bcl-2 associated X protein; Bak: Bcl-2 antagonist/killer 1 protein; cyt c: Cytochrome C; Apaf-1: Apoptosis protease activating factor-1; casp: Caspase; FADD: Fas-associated death domain; Bcl-2: B-cell lymphoma 2; AMPK: AMP-activated protein kinase; mTOR: Mammalian target of rapamycin; ULK1: Unc-51-like kinase complex; ROS: Reactive oxygen species; MDA: Malondialdehyde; GPX4: Glutathione peroxidase 4; circHIPK3: One of the most abundant circRNA in muscle; FOXO3a: A transcription factor of the O subclass of the forkhead family; LncRNA: Long non-coding RNAs; KLF3-AS1: Localize at chromosome 4p14 according to the exocarta database; mTOR: Mammalian target of rapamycin; ULK1: Atg1/unc-51-like kinase; LC3: Light chain 3; PI3K: Beclin-1/class III phosphatidylinositol 3-kinase; CMA: Chaperone-mediated autophagy; Hsc 70: Heat shock cognate71 kDa protein; LAMP2A: Lysosomal-associated membrane protein type 2; Atg: Autophagyassociated gene; Atg6: Vps34/Beclin-1; PIP3: Phosphatidylinositol (3,4,5) P3; PE: Phosphatidyl ethanolamine; SSCs: Spermatogonial stem cells; Nec-1: Necrostatin-1, a necroptosis inhibitor; NPSCs: Nucleus pulposus-derived stem/progenitor cells; HSP90: Heat shock protein 90; ROS: Reactive oxygen species; PCD: Programmed cell death.