Unraveling the Complexity and Advancements of Transdifferentiation Technologies in the Biomedical Field and Their Potential Clinical Relevance

Purusottam Mishra; Izabella Biesiada; Payal Gupta; Saeid Ghavami; Jarosław Markowski; Marek J. Łos

doi:10.2478/aite-2025-0001

Figures & Tables

Illustration of the processes of Td, differentiation, and reprogramming. The respective details could be found in the text below. Td, transdifferentiation.

Transdifferentiation of two different cells, astrocytes and fibroblasts cell, into neurons using two different methods. Astrocytes are transdifferentiated into neurons using different TFs (Ascl1, Myt1l, Brn2a, and Neuro D1), while fibroblasts transdifferentiated into neurons using small molecules (ISX9 and VPA). ASCL1: Achaete-scute homolog 1; ISX9, A neurogenesis-promoting small molecule; TFs, transcription factors; VPA, Valproic acid.

Different intermediate states during the transdifferentiation. MX, UI, and PG denote the mix, unspecific, and progenitor intermediate states, respectively.

Summary of different applications of transdifferentiation in tissue engineering, cellular therapy, disease modeling, and gene correction. Df, differentiation; iPSC, induced pluripotent stem cells; Td, transdifferentiation.

Features and pitfalls of different strategies of transdifferentiation

Strategy	Advantages	Disadvantages	References
TFs	High efficacy rate Well studied technique Direct specific reprogramming of donor cells	Risk of tumorigenicity due to insertion mutagenesis Requires genetic manipulation Limited knowledge of cell type and TF combination	Zhang et al. 2023b
MicroRNA	Non genetic strategy Specific gene expression	Lower efficiency Difficult to study the cross talks between microRNA and genes Potential risk of tumorigenicity	Shen et al., 2023; Singh et al., 2020
Small molecules or pharmacological agents	Broad range of alternatives Non-genetic approach Lower chance of tumor formation Cost-effective	Extensive optimization and specific molecule identification are necessary Toxicological effects need to be determined	Jayawardena et al. 2012; Zhang et al. 2023b
Extracellular vehicles and 3D culture	Mimics developmental process and architectural arrangement Signal transducing agents and growth factors are used	Variability in differentiated cell population and phenotype Difficult to maintain 3D structure during cell culture	Zhang et al. 2023b

Examples of transdifferentiation of different cell types using various approaches

Source cell	Target cell	TF or transdifferentiation factor used	Observation	References
Adipocyte-derived stem cells	Osteoblasts	Streptomycin, penicillin, amphotericin B, and amphotericin B with Cu²⁺	Exposure of amphotericin B induced the osteogenesis of stem cells	Skubis et al. 2017
Astrocyte	iN	Ascl1, Myt1l, Brn2a	Efficacy 0.4%–5.9%	Torper et al. 2013
Astrocyte NG2 cell	iN	NeuroD1	Transdifferentiated iN observed in tissue Efficacy 90%	Guo et al. 2014
Cardiac fibroblast	Cardiomyocytes	Gata4, Mef2c, Tbx5	Decreased infarct dimension Cardiac tissue dysfunction reduced Efficacy 10%–15%	Qian et al. 2012
Cardiac fibroblast	Cardiomyocytes	Gata4, Mef2c, Tbx5	Cardiomyocyte cells observed in fibrotic area Efficacy 3%–7%	Inagawa et al. 2012
Cardiac fibroblast	Cardiomyocytes	microRNAs 1, 133, 208, and 499	Transdifferentiated cells were observed in the infarct spot Efficacy 12%–25%	Jayawardena et al. 2015
Fibroblasts	Neurons	VPA	Neurons generated by histone deacetylase inhibitor mechanism Glutamatergic neurons generated	Hu et al. 2015a
Fibroblasts	Neurons	ISX9	Inhibition of the BET family protein induces the transdifferentiation process	Li et al. 2015
Fibroblasts	Cardiomyocytes	LIF	Transdifferentiation occurs through an intermediate state	Fu et al. 2015
Fibroblasts	Hepatocytes	HGF	Human hepatic progenitors proliferate for at least 10 passages without losing differentiation potential in vitro	Kim et al. 2019
Fibroblast	Corneal epithelial	TCF4, C/EBPδ, ∆Np63α and Corneal specific medium	Infection with TCF4, C/EBPδ, and ∆Np63α TFs and exposure of medium induce transdifferentiation	Cieślar-Pobuda et al. 2016

List of selected clinical trials involving iPSCs or iPSC reprogramming for treatment of various diseases

NCT number	Title of study	Disease	Location of study
NCT04476225	iPSCs for disease research	Hirschsprung disease	San Francisco, California, USA
NCT03883750	iPSCs for Niemann–Pick disease	Niemann–Pick disease	Lahore, Pakistan
NCT02720939	ASD-specific iPSCs for disease modeling	Autism spectrum disorder	Taipei, Taiwan
NCT02084407	Induction of pluripotent stem cells from human fibroblasts of DM1 patients	Myotonic dystrophy	Paris, France
NCT05616338	Modeling bronchial epithelium in severe asthma with human induced iPSC	Severe asthma	Montpellier, France
NCT01943383	Pharmacogenomic evaluation of antihypertensive responses in iPSCs study	Hypertension	Gainesville, Florida, USA
NCT02193724	Feasibility of generating pluripotent stem cells from patients with familial retinoblastoma	Retinoblastoma	Memphis, Tennessee, USA
NCT03872713	Establishment of human cellular disease models for Morquio disease	Morquio disease	Lahore, Pakistan
NCT03867526	Establishment of human cellular disease models for Wilson disease	Wilson disease	Lahore, Pakistan
NCT03696628	Modeling and pharmacological targeting of genetic cardiomyopathy in children via cardiomyocytes derived from iPSCs	Cardiomyopathy, familial	Montpellier, Occitanie, France
NCT01808729	CAUSE Trial: Patient specific-cellular characterization of fibromuscular dysplasia and high-risk atherosclerotic endothelium	Early onset CAD fibromuscular dysplasia	New York, New York, USA
NCT02162953	Stem cell models of best disease and other retinal degenerative diseases	Adult onset vitelliform, macular dystrophy, autosomal dominant vitreoretinochoroidopathy, best vitelliform macular dystrophy, bestrophinopathy, retinal disease	Rochester, Minnesota, USA
NCT00953693	Patient specific iPSCs	Eye disorders Hepatic disorders	Tehran, Iran,
NCT02464956	Production of iPSC-derived (RPE) cells for transplantation in AMD	AMD	Location not provided
NCT03754088	In vitro model of the cystic fibrosis bronchial epithelium via iPS technology	Cystic fibrosis

Unraveling the Complexity and Advancements of Transdifferentiation Technologies in the Biomedical Field and Their Potential Clinical Relevance

Figures & Tables

Fig 1.

Fig 2.

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Features and pitfalls of different strategies of transdifferentiation

Examples of transdifferentiation of different cell types using various approaches

List of selected clinical trials involving iPSCs or iPSC reprogramming for treatment of various diseases

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