Abstract
The transcription factor “Kruppel-like factor 4” (KLF4) is a central player in the field of pluripotent stem cell biology. In particular, it was put under the spotlight as one of the four factors of the cocktail originally described for reprogramming into induced pluripotent stem cells (iPSCs). In contrast, its possible functions in native tissue stem cells remain largely unexplored. We recently published that KLF4 is a regulator of “stemness” in human keratinocytes. We show that reducing the level of expression of this transcription factor by RNA interference or pharmacological repression promotes the ex vivo amplification and regenerative capacity of two types of cells of interest for cutaneous cell therapy: native keratinocyte stem and progenitor cells from adult epidermis, which have been used for more than three decades in skin graft bioengineering, and keratinocytes generated by the lineage-oriented differentiation of embryonic stem cells (ESCs), which have potential for the development of skin bio-bandages. At the mechanistic level, KLF4 repression alters the expression of a large set of genes involved in TGF-β1 and WNT signaling pathways. Major regulators of TGF-β bioavailability and different TGF-β receptors were targeted, notably modulating the ALK1/Smad1/5/9 axis. At a functional level, KLF4 repression produced an antagonist effect on TGF-β1-induced keratinocyte differentiation.
Highlights
The transcription factor “Kruppel-like factor 4” (KLF4) is a central player in the field of pluripotent stem cell biology
In addition to native keratinocytes extracted from skin biopsies, keratinocytes produced by the lineage-oriented differentiation of embryonic stem cells (ESCs) may constitute a complementary cell source, as they have the potential to generate three-dimensional (3D) epidermis organoids [5]
The KLF family is involved in the regulation of self-renewal and immaturity in ESCs [9], and KLF4 is one of the four factors of the reprogramming cocktail originally described for the generation of induced pluripotent stem cells (iPSCs) [10]
Summary
This perspective provides a highlight on a recent publication of our group in Nature Biomedical. Human epidermis is naturally endowed with remarkable capacities for renewal and regeneration, due to the presence of resident epithelial stem cells within its keratinocyte basal layer These capacities have enabled the development of different research and clinical models of skin organoids, including skin substitutes that have proved efficient for more than three decades in their use as a treatment for severely burned patients by autologous grafts [2,3]. Native keratinocytes extracted from adult skin biopsies currently constitute the major source of keratinocytes for medical uses They have been used for more than three decades for the bioengineering of grafts intended for the treatment of severe burns, and more recently for gene therapy. Pluripotency-induced stem cells (iPSCs), which are obtained by reprogramming adult cells (for example, fibroblasts or skin keratinocytes), can be differentiated into keratinocytes
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