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Differentiation of pluripotent stem cells for modeling human skin development and potential applications.

ABSTRACT: The skin of mammals is a multilayered and multicellular tissue that forms an environmental barrier with key functions in protection, regulation, and sensation. While animal models have long served to study the basic functions of the skin in vivo, new insights are expected from in vitro models of human skin development. Human pluripotent stem cells (PSCs) have proven to be invaluable tools for studying human development in vitro. To understand the mechanisms regulating human skin homeostasis and injury repair at the molecular level, recent efforts aim to differentiate PSCs towards skin epidermal keratinocytes, dermal fibroblasts, and skin appendages such as hair follicles and sebaceous glands. Here, we present an overview of the literature describing strategies for human PSC differentiation towards the components of skin, with a particular focus on keratinocytes. We highlight fundamental advances in the field employing patient-derived human induced PSCs (iPSCs) and skin organoid generation. Importantly, PSCs allow researchers to model inherited skin diseases in the search for potential treatments. Skin differentiation from human PSCs holds the potential to clarify human skin biology.

SUBMITTER: Oceguera-Yanez F

PROVIDER: S-EPMC9728031 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Differentiation of pluripotent stem cells for modeling human skin development and potential applications.

Oceguera-Yanez Fabian F Avila-Robinson Alfonso A Woltjen Knut K

Frontiers in cell and developmental biology 20221123

The skin of mammals is a multilayered and multicellular tissue that forms an environmental barrier with key functions in protection, regulation, and sensation. While animal models have long served to study the basic functions of the skin in vivo, new insights are expected from in vitro models of human skin development. Human pluripotent stem cells (PSCs) have proven to be invaluable tools for studying human development in vitro. To understand the mechanisms regulating human ...[more]

PMID: 36506084

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Project description:BackgroundHuman induced pluripotent stem cells (hiPSCs) offer a renewable source of cells for the generation of hematopoietic cells for cell-based therapy, disease modeling, and drug screening. However, current serum/feeder-free differentiation protocols rely on the use of various cytokines, which makes the process very costly or the generation of embryoid bodies (EBs), which are labor-intensive and can cause heterogeneity during differentiation. Here, we report a simple feeder and serum-free monolayer protocol for efficient generation of iPSC-derived multipotent hematoendothelial progenitors (HEPs), which can further differentiate into endothelial and hematopoietic cells including erythroid and T lineages.MethodsFormation of HEPs from iPSCs was initiated by inhibition of GSK3 signaling for 2 days followed by the addition of VEGF and FGF2 for 3 days. The HEPs were further induced toward mature endothelial cells (ECs) in an angiogenic condition and toward T cells by co-culturing with OP9-DL1 feeder cells. Endothelial-to-hematopoietic transition (EHT) of the HEPs was further promoted by supplementation with the TGF-β signaling inhibitor. Erythroid differentiation was performed by culturing the hematopoietic stem/progenitor cells (HSPCs) in a three-stage erythroid liquid culture system.ResultsOur protocol significantly enhanced the number of KDR+ CD34+ CD31+ HEPs on day 5 of differentiation. Further culture of HEPs in angiogenic conditions promoted the formation of mature ECs, which expressed CD34, CD31, CD144, vWF, and ICAM-1, and could exhibit the formation of vascular-like network and acetylated low-density lipoprotein (Ac-LDL) uptake. In addition, the HEPs were differentiated into CD8+ T lymphocytes, which could be expanded up to 34-fold upon TCR stimulation. Inhibition of TGF-β signaling at the HEP stage promoted EHT and yielded a large number of HSPCs expressing CD34 and CD43. Upon erythroid differentiation, these HSPCs were expanded up to 40-fold and displayed morphological changes following stages of erythroid development.ConclusionThis protocol offers an efficient and simple approach for the generation of multipotent HEPs and could be adapted to generate desired blood cells in large numbers for applications in basic research including developmental study, disease modeling, and drug screening as well as in regenerative medicine.

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Differentiation of pluripotent stem cells for modeling human skin development and potential applications.

Publications

Differentiation of pluripotent stem cells for modeling human skin development and potential applications.

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