KLF4 inhibition promotes the expansion of keratinocyte precursors from adult human skin and of embryonic-stem-cell-derived keratinocytes

Regenerative medicine aims to repair damaged, tissues or organs for the treatment of various diseases, which have been poorly managed with conventional drugs and medical procedures. To date, multimodal regenerative methods include transplant of healthy organs, tissues, or cells, body stimulation to activate a self-healing response in damaged tissues, as well as the combined use of cells and bio-degradable scaffold to obtain functional tissues. Certainly, stem cells are promising tools in regenerative medicine due to their ability to induce de novo tissue formation and/or promote organ repair and regeneration. Currently, several studies have shown that the beneficial stem cell effects, especially for mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) in damaged tissue restore are not dependent on their engraftment and differentiation on the injury site, but rather to their paracrine activity. It is now well known that paracrine action of stem cells is due to their ability to release extracellular vesicles (EVs). EVs play a fundamental role in cell-to-cell communication and are directly involved in tissue regeneration. In the present review, we tried to summarize the molecular mechanisms through which MSCs and iPSCs-derived EVs carry out their therapeutic action and their possible application for the treatment of several diseases.

Section: Stem Cells and Regenerative Medicinementioning

confidence: 99%

Mesenchymal and Induced Pluripotent Stem Cells-Derived Extracellular Vesicles: The New Frontier for Regenerative Medicine?

Barreca

Cancemi

Geraci

2020

“…This perspective provides a highlight on a recent publication of our group in Nature Biomedical Engineering [ 1 ]. 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.…”

Section: Biomedical Contextmentioning

confidence: 99%

“…The regulatory functions of the transcription factor KLF4 have been firstly investigated in “holoclone” keratinocytes [ 1 ], which are representative of an immature population of cultured precursors containing functional stem and progenitor cells [ 15 ]. These cells correspond to the clonal progeny of single keratinocyte stem cells that were functionally characterized by their extensive growth potential exceeding 100 population doublings through successive subcultures, and the capacity for epidermis reconstruction in vitro and regeneration in vivo.…”

Section: Klf4 Functions In Native Adult Keratinocytesmentioning

confidence: 99%

“…To widen the perspectives that may emerge from the concept of KLF4 repression in keratinocyte stem cells, the effects of transient KLF4 downmodulation were also studied on bioengineered keratinocytes obtained by the lineage-oriented differentiation of human ESCs (Ker-ESCs) [ 1 ]. Although Ker-ESCs can ensure the reconstruction of correctly differentiated 3D epidermises [ 5 ], they do not reproduce all the characteristics of native keratinocytes.…”

Section: Extrapolation To Esc-derived Keratinocytesmentioning

confidence: 99%

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When the Search for Stemness Genes Meets the Skin Substitute Bioengineering Field: KLF4 Transcription Factor under the Light

Fortunel

Martin

2020

Self Cite

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 TGFβ1-induced keratinocyte differentiation.

“…In skin, human 3D organoids have demonstrated efficiency in the modeling of pathophysiological contexts, such as defects in the epidermal barrier associated with atopic dermatitis [8], or epidermal cancer proneness in xeroderma pigmentosum [9]. Notably, bioengineered 3D epidermises have contributed to the knowledge of keratinocyte stem and progenitor cells [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Exposure of Human Skin Organoids to Low Genotoxic Stress Can Promote Epithelial-to-Mesenchymal Transition in Regenerating Keratinocyte Precursor Cells

Cavallero

Granito

Stockholm

et al. 2020

Self Cite

For the general population, medical diagnosis is a major cause of exposure to low genotoxic stress, as various imaging techniques deliver low doses of ionizing radiation. Our study investigated the consequences of low genotoxic stress on a keratinocyte precursor fraction that includes stem and progenitor cells, which are at risk for carcinoma development. Human skin organoids were bioengineered according to a clinically-relevant model, exposed to a single 50 mGy dose of γ rays, and then xeno-transplanted in nude mice to follow full epidermis generation in an in vivo context. Twenty days post-xenografting, mature skin grafts were sampled and analyzed by semi-quantitative immuno-histochemical methods. Pre-transplantation exposure to 50 mGy of immature human skin organoids did not compromise engraftment, but half of xenografts generated from irradiated precursors exhibited areas displaying focal dysplasia, originating from the basal layer of the epidermis. Characteristics of epithelial-to-mesenchymal transition (EMT) were documented in these dysplastic areas, including loss of basal cell polarity and cohesiveness, epithelial marker decreases, ectopic expression of the mesenchymal marker α-SMA and expression of the EMT promoter ZEB1. Taken together, these data show that a very low level of radiative stress in regenerating keratinocyte stem and precursor cells can induce a micro-environment that may constitute a favorable context for long-term carcinogenesis.