Engineering considerations of iPSC-based personalized medicine

Park, Sangbae; Gwon, Yonghyun; Khan, Shahidul Ahmed; Jang, Kyoung-Je; Kim, Jangho

doi:10.1186/s40824-023-00382-x

Biomaterials Research

Table 2 Application of engineered iPSCs for personalized medicine

From: Engineering considerations of iPSC-based personalized medicine

Applications	Engineering Strategy	Cell Types	Targets	Features	Outcomes	References
Tissue Regeneration	Paracrine Effects	Cardiac Cells	Cardiac tissue	Increased angiogenic potential, secretion proangiogenic and proinflammatory cytokines	Recovery from human acute myocardial infarction	[120]
		Cardiac Cells	Cardiac tissue	Up to 80% of cardiomyocyte differentiation was increased by Wnt treatment	Cardiomyocyte differentiation through paracrine factors	[121]
		Cardiac Cells	Cardiac tissue	Enhancement of promigratory, proangiogenic, and antiapoptotic	Effective recovery of damaged myocardium	[112]
		Cardiac Cells	Cardiac tissue	Secretome suppressed apoptotic cardiomyocytes > 70% locally	Heart muscle extracellular signals for cell-free treatment	[122]
		Neurons and glial cells	Neuron tissue	The Ang 1–7/Mas receptor inhibited aging and decreased neurodegenerative susceptibility	Therapeutic strategies for Parkinson’s disease	[123]
		Neurons and glial cells	Neuron tissue	Iinduced neurotrophic and neuroprotective effects and decreased the number of necrotic and apoptotic cells	encourage the development and expansion of neurites	[124]
		Neurons cells	Neuron tissue	Resource for transcriptomics on corticogenesis in 5 situations	Neurons were variable, and more developed	[125]
		Renal cells	Kidney tissue	Microbioreactor array–based multicellular differentiation	Identification of renal cells	[126]
		Murine bone cells	Bone tissue	Expression of the osteogenic genes via paracrine mechanisms	BMP-2, BMP-4, and BMP-6 gene expression is increased	[91]
		Hepatic cells	Liver tissue	The Transwell system of HE-iPSCs was separately co-cultured with MSCs and/or HUVECs	Regulate the differentiation of human hepatocytes	[127]
	Differentiation	Vascular smooth muscle cell	Vascular grafts tissue	Incorporating biodegradable scaffolds, progressive pulsatile stretching	Non-immunogenic, cellularized vascular grafts	[128]
		Vascular smooth muscle cell	Vascular tissue	PGA scaffolds express mature VSMC marker	Formation of autologous human vascular tissues	[129]
		Cardiac Cells	Cardiac tissue	Human endothelial cell patches and cell-free patches	Electrical coupling improved left ventricular function by 31%	[130]
		Cardiac and endothelial cells	Cardiac tissue	A cardiac muscle patch was created by 3D printing a scaffold with seeding cardiomyocytes and smooth muscle cells	Cell engraftment was 24.5% at week 1 and 11.2% at week 4 than cell-free scaffolds	[131]
		Lymphoblastoid cells	Cardiac tissue	Modifiable DNA methylation, chromatin accessibility, and gene expression levels	Identify the impact of chromatin accessibility specific to different cell types	[132]
		Mesodermal cells	Muscle tissue	Dystrophic mice's hearts and skeletal muscles can successfully engraft with human MiPSC	Cocktails of miRNA encourage myogenesis	[133]
		Endothelial cells	Lung tissue	Enhancing endothelial colony forming cells-built lung scaffolds with 8CPT-2Me-cAMP	Improved endothelial functionality	[134]
		hiPSC lines	Endoderm	Endoderm differentiation using a single-cell RNA-based population	Used for genetic background variability assessment	[135]
		iPSC-derived MSCs	Bone tissue	Better osseous consolidation was seen with HFF-iMSC + CPG transplantation compared with CPG alone	Express of osteopontin and bone morphogenic proteins	[136]
		Endothelial cells	Endothelial tissue	Medium supplemented VEGF is differentiated into endothelial cells	Functional cues to promote cell attachment, survival, and differentiation	[137]
		hiPSCs	Inner ear hair cells	Using CRISPR/Cas9, the MYO15A mutation was genetically fixed, saving the morphology and function	Gene mutation-based deafness can be functionally restored	[138]
	Biomodulation	hiPSCs	Footprint-free MSCs	Wnt3a, Activin A, and BMP4 had synergistic effects on MSC after just 4 days of therapy and microbead encapsulation	Create osteogenesis, chondrogenesis, and adipogenesis lineages without teratoma development in vivo	[139]
		MSCs	Bone tissue	Scaffolds: GO was cross-linked with N-hydroxy succinimide and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride	Less than 0.5% GO was biocompatible and encouraged osteogenesis and proliferation	[140]
		MSCs	Cardiac tissue	Direct injection of saline 2 × 10⁸ hESC-CMs or 2 × 10⁸ hiPSC-MSCs into the myocardium	No proarrhythmia or tumor formation and improvement of cardiac function	[141]
	Pharmaceuticals	iPSC-derived EVs	Neuron tissue	Electroacupuncture and iPSC-derived extracellular vesicles on mice with ischemic stroke	Treatment for ischemic stroke and damaged tissues	[142]
		iPSC-derived EVs	Neuron tissue	Motor neurons load mRNAs into EVs to control specific processes	Differentiated into motor neurons	[115]
		Cardiac Cells	Cardiac tissue	Post-infarction remodeling, extracellular vesicles released by ISX-9-induced CPCs	Increased angiogenesis, cardiomyocyte proliferation, and used in heart infarction treatment	[143]
Cancer Therapy	Paracrine Effects	Endothelial cells	Breast cancer	Organotypic microfluidic model of human vasculature upregulated secreted factors during cancer cell extravasation	Increased levels of IL-6, IL-8, and MMP-3 and assessment of therapeutic drugs in cancer metastasis	[144]
		iPSC	Cell-derived tumors	Hypoxia-inducible factor-1-alpha-regulated matrix metalloproteinases operate as a mediator downstream of mTORC1	Development of stem cell-derived tumors	[145]
		iPSC	Osteosarcoma	The tumorigenic potential is repressed by suppression of SFRP2, FOXM1, or CYR61	A potential treatment approach is to suppress SFRP2	[146]
	Differentiation	Antigen-specific T cells	Xenograft cancer models	Differentiating CD8ab T cells into antigen-specific TCR	impede the growth of tumors in xenograft cancer models	[147]
		Mouse iPSCs	Tumor vasculature	The recruitment of host endothelium vessels into the tumor is aided by cancer stem cells	Investigate the tumor vasculature and create fresh approaches to targeting	[148]
		Cardiac Cells	Breast Cancer	Without causing cardiomyocyte death, clinically relevant doses of trastuzumab reduced the iPSC-CMs' ability to contract and handle calcium	Mechanism behind the emergence of heart dysfunction is changes in cellular metabolic pathways	[149]
	Biomodulation	NK cells	Ovarian cancer xenograft mode	Comparing T-CAR-expressing iPSC-derived NK cells and non-CAR-expressing cells, CAR exhibit antitumor efficacy	"Off-the-shelf" targeted lymphocytes for immunotherapy against cancer	[18]
		NK cells	Tumor lysis	Enhance cytokines, cytotoxicity against solid and hematologic malignancies, and attracted T cells and anti-PD-1 antibodies	Encouraging the infiltration of T cells to enhance checkpoint inhibitor treatments	[107]
		NK cells	NK cells mediated tumor	Through the expression of CD16A, CD64/16A, and the altered NK cells, tumor cell death was mediated	IgG Fc chimeric proteins and therapeutic mAbs with switchable targeting components	[150]
		Macrophages	Removal cancer cells	CAR expression improves tumor cell phagocytosis, polarizes macrophages, and secretes cytokines	Utilized to eliminate cancer cells	[113]
		Macrophages	Disease models	iPSC line SFCi55-ZsGreen is used to produce terminally differentiated macrophages	Used to track disease model progression in vivo	[151]
		MSCs	in vitro and in vivo Anti-tumor effects	Through apoptotic signaling pathways, TRAIL-iMSCs reduced tumor growth in xenografts of the A549 or MCF-7	High homogeneity therapeutic gene-targeted MSCs for cancer treatment	[152]
		MSCs	Facial Tumor	iMSCs were differentiated by transforming growth factor beta/activin signaling pathway inhibition	Immunomodulatory and anti-inflammatory	[153]
		Cytotoxic T lymphocytes	Cervical cancer	Revealed strong cytotoxicity against cervical cancer after differentiating into HPV16-specific regenerated CTLs	Tumors overwhelm result on epithelial cancers	[154]
Drug Development	Paracrine Effects	Cardiac Cells	Cardiovascular disease	H9C2 cells are protected against stress-induced senescence by blocking the p53-p21 and p16-pRb pathways	Therapeutic approach for cardiovascular disease	[155]
	Differentiation	iPSCs and ESCs	Blood cells	Mature blood cells are formed in part by chromatin state, DNA methylation, and gene expression	the best way to choose iPSCs for clinical purposes	[156]
		iPSCs	Hepatocytes and adipocytes	Transcriptomic and metabolomic effects of the 1p13 rs12740374 variation on cardiometabolic markers	Tools for GWAS variant validation	[157]
		iPSCs	Hematopoietic cells	DNA methylation and gene expression patterns associated with leukemia	Examining the clonal characteristics of human AML	[158]
		iPSCs	Microglia	Exposure to certain stimuli and co-culture with astrocytes to induce microglial differentiation	Similar functional traits of isolated Microglia from the brain	[159]
	Biomodulation	iPSCs	Hematopoietic cells	Myeloid malignancy is caused by the chromosome 7q loss and the splicing factor SRSF2 P95L mutation	Drug discovery and testing are done with hematopoietic cells	[160]
		iPSC-derived MSCs	Immunomodulatory effects	T cell responses as an action of soluble factors and inhibiting the cleavage of caspases	Immunomodulatory effects on T cell responses	[161]
		iPSCs	Strong immunomodulatory	Decreased c-Myc expression and downregulation of the DNA replication pathway	Low oncogenicity and strong immunomodulatory, good potential for therapeutic use	[162]
		Ligament and gingival Cells	iPSC-MSC	To raise the number of Treg cells while decreasing the number of Th1/Th2/Th17 populations and T-cell effectors	Clinical use in therapeutic applications and potent immunosuppressive properties	[163]
		MSCs	Myocardial infarction	Intravenous infusion of 5 × 10⁵ or 1 × 10⁶ hiPSC-CMs	enhance cardiac function in myocardial infarction	[164]
	Pharmaceuticals	Liver cells	Liver diseases	Apolipoprotein B synthesis is inhibited by cardiac glycosides	Treatments for inborn errors of hepatic metabolism	[114]
		Liver cells	Liver fibrosis	qHSC-like cells converted into activated HSCs in culture	Investigate the therapeutic compounds connected to HSCs'	[165]
		Liver cells	Liver injury	Identified key drug transporters and metabolizing enzymes	Utilized in tests for toxicity, excretion, and metabolism	[166]
		Liver cells	Hepatotoxicity assessment	Using confocal and 3D image analysis, several spheroid phenotypes compared multi-parametrically	Differences between the two cell types' pharmacological effects	[167]
		Liver and cardiac cell	Drug efficacy, and toxicity assessment	By the cytochrome P450 enzyme in the liver MPS, cisapride is metabolically converted to nonarrhythmogenic norcisapride	Screening of the liver and heart for medication effectiveness, and toxicity	[168]
		Neuron cells	Neurological mtDNA Disorders	Avanafil drug partially corrects the calcium deficiency in patient NPCs and differentiated neurons	Model for testing drugs for mtDNA diseases	[169]
		Neuron cells	Alzheimer’s Disease	Topiramate is an anti-Ab cocktail comprised of a combination of 27 Ab-lowering screen hits, prioritized hits, and 6 leading compounds	Beneficial in the development of drugs for Alzheimer's disease	[170]
		Cardiac cells	Drug-induced clinical trials	Values of field potential duration prolongation and clinically concentrations were associated	Demonstrate the feasibility of in vitro preclinical studies	[171]
		Cardiac cells	Cardiac disease	Isoproterenol and verapamil 3D-printed an asymmetric, cantilever-based tissue scaffold	Drug discovery via high-throughput screening	[172]
		Macrophages	Modeling of Tissue Resident Macrophage	Growth factors and particular organ specific cues can help macrophages differentiate	iMacs with pro-inflammatory characteristics, mimicking the disease phenotype	[173]
		Cardiac cells	3D-iPSC cardiomyocyte tissues for drug development	iPSC-CM tissues offer blood capillary-like networks and synchronous beating ratios	Compared to 2D-iPSC-CM cells, 3D-iPSC-CM tissues showed hazardous reactions	[174]

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