Extensive tissue-regenerative capacity of neonatal human keratinocyte stem cells and their progeny

Li, Amy; Pouliot, Normand; Redvers, Richard P.; Kaur, Pritinder

doi:10.1172/jci200419140

Cited by 153 publications

(133 citation statements)

References 44 publications

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“…These layers of epidermis are the major contributors to tissue repair, as they have the highest proliferative capacity (63) and, therefore, can be considered as primary targets for proinflammatory molecules. Interestingly, we found that Ca 2ϩ -induced differentiation of cultured HEK leads to decreased production of cortisol (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Vukelic

Stojadinović

Pastar

et al. 2011

Journal of Biological Chemistry

173

196

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Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 ␤-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11␤-hydroxysteroid dehydrogenase 2 (11␤HSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1␤, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1␤ production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing.Acute wound healing is a complex biological process mediated by a network of signaling pathways that coordinate multiple cellular processes, including cellular migration and proliferation, ultimately leading to barrier restoration (1). Wound healing is a tightly spatiotemporally regulated process, and changes in any component of this process can be detrimental, leading to further tissue damage or impairment of healing (2, 3).For example, timing of inflammatory response is essential; proinflammatory signals are important in the early stage of healing, but they can be detrimental if they persist (4, 5), underscoring a need for tight control of both stimulators and inhibitors during the wound healing process.Upon injury, keratinocytes are the first cells that respond (6, 7) by releasing pre-stored interleukin-1 (IL-1) (8). IL-1 has an autocrine and a paracrine function; that is, to activate keratinocytes and to alert the surrounding cells and tissues. The release of IL-1 by keratinocytes, with subsequent release of additional signaling molecules (9, 10), demarcates the proinflammatory phase of wound healing. In response to these signals, activated keratinocytes start migrating and proliferating (7,8,11). Successful repair after tissue injury requires resolution of inflammatory response, transitioning keratinocyte (HEK) from activated to differentiating phenotype. However, very little is known about endogenous epidermal signals that control keratinocyte activation cycle and inflammatory response.Epidermal keratinocytes have important immunol...

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Section: Discussionmentioning

confidence: 99%

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Vukelic

Stojadinović

Pastar

et al. 2011

Journal of Biological Chemistry

173

196

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“…Despite the significant progress made in this area, reliable identification criteria to distinguish between stem and nonstem epidermal cells are still lacking. [30][31][32] Thus, the use of nonintegrative vectors such as adenoviruses or the inclusion of adjustable excisional elements 25 would be safer.…”

Section: Transient Improvement Of a Local Situationmentioning

confidence: 99%

Current approaches and perspectives in human keratinocyte-based gene therapies

et al. 2004

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Inherited and acquired disorders are liable to treatment with somatic gene therapy. The skin, and in particular epidermal cells, are particularly suited to genetic manipulation and follow-up of therapeutic effects. Cutaneous gene therapy may be effective for skin defects and systemic abnormalities.The robust basic and preclinical data available today would support the application of keratinocyte-based gene therapy to patients.

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“…Experimental evidence supporting this idea was demonstrated in the conditional ability of early differentiating human keratinocytes to regenerate a stable stratified epidermis when supported by inductive dermal cells and supplemented with extracellular matrix proteins (34). When highly-inductive dermal papilla cells were implanted into split footpad skin in contact with the basement membrane, cultured dermal papilla cells could induce HF morphogenesis and hair growth in adult epidermis (35) suggesting that signals derived from fully inductive dermal papilla cells can re-program most proliferative keratinocyte populations irrespective of their previous lineage commitment.…”

Section: Epidermal Plasticity and The Skin Microenvironmentmentioning

confidence: 96%

The Skin: A Home to Multiple Classes of Epithelial Progenitor Cells

Yan

Owens

2008

Stem Cell Rev

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To maintain homeostasis in the adult skin, epithelial keratinocyte stem cells are thought to divide infrequently giving rise to short-lived (transit amplifying) cells that undergo a limited number of cell divisions and ultimately terminal differentiation. This model for the epidermal stem cell niche has increased in complexity by the multiple putative progenitor keratinocyte populations that have recently been identified in distinct regions of the interfollicular epidermis and hair follicle appendages. Under normal conditions, these progenitor populations are long-lived and able to sustain the cellular input to certain epidermal structures including the interfollicular epidermis and sebaceous gland. Other putative epithelial progenitors derived from the hair follicle possess high in vitro proliferative capacity and are able to regenerate skin, hair and sebaceous lineages in transplantation studies. These new findings present the cutaneous epithelium as a highly compartmentalized structure potentially maintained by multiple classes of progenitor cells. In this review, we will discuss the implications of these new putative epithelial progenitor populations and their potential to be influenced by external stimuli for skin homeostasis and carcinogenesis.

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Extensive tissue-regenerative capacity of neonatal human keratinocyte stem cells and their progeny

Cited by 153 publications

References 44 publications

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury

Current approaches and perspectives in human keratinocyte-based gene therapies

The Skin: A Home to Multiple Classes of Epithelial Progenitor Cells

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