Table 2.

Different strategies of UiPSCs/UiNSCs reprogramming and the generation of disease-specific UiPSCs

UiPSCs/UiNSCs reprogramming	Reprogramming strategies	Factors	Diseases (mutations)	Major findings	References
UiPSCs	Retrovirus	OSKM	N.A	First reported method to generate UiPSCs with reprogramming efficiency up to 4%	[32, 52]
			Paroxysmal kinesigenic dyskinesia (PKD) (Proline-rich transmembrane protein 2 (PPRT2) c.649dupC mutation)	PRRT2 mRNA was reduced in PKD-UiPSCs PKD-UiPSCs were able to differentiate into functional glutamatergic, dopaminergic, and motor neurons in vitro	[59]
			X-linked Danon disease (nonsense mutation of the LAMP-2 gene (c.520c > T, exon 4)	Patients’ iPSC-cardiomyocytes (CMs) lines were generated Administration of the DNA demethylation agent 5-aza-2’-deoxycytidine reactivated the silent LAMP2 allele in patients’ iPSCs and iPSC-CMs and ameliorated their autophagy failure	[60]
	Lentivirus	OSKM	Systemic lupus erythematosus (SLE)	SLE patients-UiPSCs were generated	[62]
			Cryptorchid (Cryp) (mutations in insulin-like factors 3, zinc finger (ZNF) 214 and ZNF 215 genes)	Cryp-UiPSC lines were generated	[63]
			Spinal muscular atrophy (SMA) (mutations of the survival motor neuron 1 (SMN1) gene)	The neurite outgrowth was reduced in both SMA type I and III-UiPSCs derived motor neurons (MNs) Significant hyperexcitability was detected in SMA type I-UiPSCs derived MNs, but not in SMA type III-UiPSCs derived MNs	[17]
	Sendai Virus	OSKM	Attention deficit hyperactivity disorder (ADHD) type 2 diabetes mellitus	ADHD-UiPSCs were generated	[67]
			Obsessive compulsive disorder (OCD)	OCD-UiPSCs were generated	[68]
			Duchenne Muscular Dystrophy (DMD) (dystrophin/deletion of exon 50)	DMD-UiPSCs were generated and can be differentiated into cardiomyocytes	[69]
			DMD (DMD/c.497G > T; p.G166V)	DMD-UiPSCs were generated	[70]
			DMD (dystrophin/deletion of exon 50) (CRISPR-CAS9 generation of c.263delG in the dystrophin gene)	Reduced myofibril contractile tension, slower relaxation kinetics, and Ca2+ handling abnormalities	[71]
			Dilated cardiomyopathy (DCM)	DCM-UiPSCs were generated	[72]
			Heterozygous for a dinucleotide insertion within exon 4 of PAI-1 gene	PAI-1-UiPSCs were generated	[92]
			Ventricular septal defect (VSD) (ryanodine receptor 2 (RyR2) mutation (c.7448 T > G, p.L2483R)	VSD-UiPSCs were able to differentiate into cardiomyocytes but had a higher level of autophagy	[74]
			X-linked Alport syndrome (X-LAS) (Hemizygous COL4A5 gene mutation p.G1433V (c.4298G > T)	X-LAS-UiPSCs were generated	[75]
			Spinal cord injury (SCI)	SCI UiPSCs-derived neural progenitor cells were able to give rise to neurons, oligodendrocytes, and astrocytes. Grafted neural progenitor cells into the injured spinal cord survived and differentiated into neurons and glia	[76]
		OSK, SV40, miR302-367	Spinal muscular atrophy (homozygous deletion of exon 7 and exon 8 of the SMN1 gene)	Conversion of the SMN2 gene to an SMN1-like gene in SMA-UiPSCs using CRISPR/Cpf1 and single-stranded oligodeoxynucleotide in UiPSCs restored SMN expression and MN differentiation	[93]
		SeV, KOS, Klf4 and c-Myc	Type 2 diabetes mellitus (T2DM)	T2DM-UiPSCs differentiated into neuron, astrocyte, and microvascular endothelial cells	[77]
	Episomal vectors	OSK and SV40LT	Hemophilia A (HA)	HA-UiPSCs-derived hepatocytes failed to produced clotting factor VIII (FVIII)	[94]
		OSK, SV40T and miR-302-367	Hemophilia A, Hemophilia B, Amyotrophic lateral sclerosis (ALS), Systemic lupus erythematosus, β-thalassemia	Patients-UiPSCs were generated	[80]
		OSKM	Down syndrome (DS) (Trisomy 21-(T21)	T21-UiPSCs maintained chromosomal stability for more than 20 passages and were more sensitive to proteotoxic stress than euploid iPSCs T21-UiPSCs can be differentiated into glutamatergic neurons and cardiomyocytes	[84]
		OSK and miR-302-367	Phenylketonuria (PKU)	PKU-UiPSCs were generated	[73]
		OSKM, LIN28, NANOG and SV40LT with miR302/367	PCSK9-mediated autosomal dominant hypercholesterolemia (PCSK9-S127R (ADH) and R104C/V114A (FHBL) mutations)	PCSK9-UiPSCs differentiated into hepatocyte-like cells ADH-derived cells secreted less amount of PCSK9 with a reduction in low-density lipoprotein (LDL) uptake FHBL-derived cells showed a strong dcreased in PCSK9 secretion and an increase in LDL uptake Pravastatin treatment enhanced LDL receptor and PCSK9 mRNA expression, as well as PCSK9 secretion and LDL uptake	[43]
			Type 2 Long QT syndrome (HERG A561P mutation)	Patient-UiPSCs differentiated into CMs using the matrix sandwich method The HERG A561P mutation led to a trafficking defect with reduced delayed rectifier K+ current, resulting in action potential prolongation and arrhythmias	[85]
	Episomal with small molecules	L-Myc, OSK, Glis1, and miR-302 cluster with inhibitor of lysine-demethylase1, methyl ethyl ketone, glycogen synthase kinase 3β, and histone deacetylase	N.A	Decreased chromosomal variation and increased Sir1 expression in UiPSCs compared with iPSCs induced using the traditional episomal system	[86]
	Small molecules	cyclic pifithrin-α (a P53 inhibitor), A-83-01, CHIR99021, thiazovivin, NaB, and PD0325901	Diabetes and blood disorders	Improved the reprogramming efficiency (170-foldmore) significantly Replacement of Matrigel with autologous urine cell feeders can overcome the reprogramming failure	[87]
UiNSCs reprogramming	Small molecules with episomal vectors	CHIR99021, PD0325901, A83-01, thiazovivin, and DMH1 with OSK, SV40T, and miR-302-367 cluster	N.A	The UiNSCs can self-renew and differentiate into multiple functional neuronal subtypes and glial cells in vitro	[88]
		CHIR99021, PD0325901, A83-01, Thiazovivin with OSK, SV40LT, c-MYC, and LIN28	N.A	The UiNSCs generated were positive for NSC markers NESTIN, PAX6, SOX2, and OLIG2	[90]
	mRNA with small molecules	OSK, GLIS1 and B18R mRNAs with purmorphamine, Forskolin,Vitamin C, and Sodium Butyrate	N.A	The UiNSCs generated can differentiate into neurons, astrocytes and oligodendrocytes in vitro and in vivo	[19]