Induction of Skin-Derived Precursor Cells from Human Induced Pluripotent Stem Cells

Abstract

The generation of full thickness human skin from dissociated cells is an attractive approach not only for treating skin diseases, but also for treating many systemic disorders. However, it is currently not possible to obtain an unlimited number of skin dermal cells. The goal of this study was to develop a procedure to produce skin dermal stem cells from induced pluripotent stem cells (iPSCs). Skin-derived precursor cells (SKPs) were isolated as adult dermal precursors that could differentiate into both neural and mesodermal progenies and could reconstitute the dermis. Thus, we attempted to generate SKPs from iPSCs that could reconstitute the skin dermis. Human iPSCs were initially cultured with recombinant noggin and SB431542, an inhibitor of activin/nodal and TGFβ signaling, to induce neural crest progenitor cells. Those cells were then treated with SKP medium that included CHIR99021, a WNT signal activator. The induction efficacy from neural crest progenitor cells to SKPs was more than 97%. No other modifiers tested were able to induce those cells. Those human iPSC-derived SKPs (hiPSC-SKPs) showed a similar gene expression signature to SKPs isolated from human skin dermis. Human iPSC-SKPs differentiated into neural and mesodermal progenies, including adipocytes, skeletogenic cell types and Schwann cells. Moreover, they could be induced to follicular type keratinization when co-cultured with human epidermal keratinocytes. We here provide a new efficient protocol to create human skin dermal stem cells from hiPSCs that could contribute to the treatment of various skin disorders.

Advances of Stem Cell Therapeutics in Cutaneous Wound Healing and Regeneration

“…The unique reprogramming of iPSC technology made it possible to generate genetically diverse patient-specific cell lines from genetic skin disorders or chronic wounds which have tremendous potential for disease modeling and drug screening [ 59 , 60 ]. During the last decade, significant progress has been made in the differentiation of the mouse, human iPSCs in to dermal stem cells and hair follicle lineages [ 58 , 61 ], mesenchymal cells with the potential of forming dermal papilla [ 62 ], fibroblasts [ 63 ], melanocytes [ 64 ], keratinocytes [ 65 , 66 ], among others. The multipotent capacity with limited immunoreactivity of iPSCs makes them a prospective agent for treating chronic skin disorders and unresolved wounds [ 67 ].…”

The Human Skin-Derived Precursors for Regenerative Medicine: Current State, Challenges, and Perspectives

“…However, the identity of monolayer-derived hSKPs remained ambiguous. Scholars proposed those cells as dermal mesenchymal SCs rather than traditional hSKPs [ 54 ], since dermal mesenchymal SCs were also known for self-renewal ability and neurogenic potential [ 55 , 56 ]. Induction of hSKPs from induced pluripotent SCs (iPSCs) is another hotspot.…”

Multipotentiality of skin‐derived precursors: application to the regeneration of skin and other tissues

“…SKPs are able to differentiate into other kind of mesenchymal cells such as osteocytes and chondrocytes , cells constituting bones and cartilage. Rodent and human SKPs can generate in vivo both cell types when transplanted into a tibial bone fracture model with morphological and phenotypical criteria of endogenous mesenchymal/osteogenic cells.…”

“…Adult differentiated cells retain genetic information identical to early embryonic cells . A recent study focused on the generation of SKPs from human induced pluripotent stem cells in order to reconstitute a dermis with a simple and efficient protocol . The induction of SKPs was done from human iPSCs generated by introducing four important transcription factors into human dermal fibroblasts.…”