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.
Highlights
An important goal of current bioengineering efforts is to generate or reconstitute fully organized and functional organ systems from dissociated cells that have been propagated under defined tissue culture conditions
The results revealed that CHIR successfully induced hiPSC-Skin-derived precursor cells (SKPs) in a dose-dependent manner up to 3 μM, but higher concentrations of CHIR markedly inhibited the production of hiPSC-SKPs (Fig 2A)
SKPs display the functional properties predicted of dermal Stem cells (SCs), contributing to dermal maintenance, wound-healing and hair follicle (HF) morphogenesis [23]
Summary
An important goal of current bioengineering efforts is to generate or reconstitute fully organized and functional organ systems from dissociated cells that have been propagated under defined tissue culture conditions. Stem cells (SCs) have the unique capacity to self-renew and to differentiate into the cell lineages that constitute their tissue of origin. SCs reside in a specialized environment (termed the niche) and regulate their proliferation and differentiation to maintain and regenerate tissue [1,2,3]. Epithelial SCs reside in the bulge region of the hair follicle (HF), a specialized portion of the outer root sheath epithelium defined as the insertion site of the arrector pili muscle [4,5,6,7]. Bulge cells possess the PLOS ONE | DOI:10.1371/journal.pone.0168451 December 19, 2016
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