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.

Keywords: 3D skin models; epidermal differentiation; human induced pluripotent stem cells; iPSCs; keratinocyte; skin inherited diseases; skin organoids.

FIGURE 1

Basic biology of the skin. The scheme on the left shows a sagittal section of a skin biopsy depicting the main components of the skin labelled with associated skin appendages. The scheme on the right shows a basement membrane adjacent to the interfollicular epidermis (IFE) populated by epidermal stem cells keratinocytes that differentiate to reconstitute four histologically distinct layers. The keratinocyte molecular markers characteristic of each layer are labelled on the side.

FIGURE 2

Differentiation of pluripotent stem cells to skin keratinocytes. Scheme showing the transition from a pluripotency state to epidermal keratinocytes incorporating morphogen-induction and compound induction of skin epidermis. The cell markers characteristic of the cell state is described below the drawings.