Engineered Microenvironments to Direct Epidermal Stem Cell Behavior at Single-Cell Resolution

Abstract

Mammalian epidermis is maintained through proliferation of stem cells and differentiation of their progeny. The balance between self-renewal and differentiation is controlled by a variety of interacting intrinsic and extrinsic factors. Although the nature of these interactions is complex, they can be modeled in a reductionist fashion by capturing single epidermal stem cells on micropatterned substrates and exposing them to individual stimuli, alone or in combination, over defined time points. These studies have shown that different extrinsic stimuli trigger a common outcome-initiation of terminal differentiation-by activating different signaling pathways and eliciting different transcriptional responses.

A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis

“…The key role of DUPS6 at commitment fits well with its upregulation by Serum Response Factor, which is known to control keratinocyte differentiation 14 and the importance of DUSP6 in controlling the activation kinetics and dose-response behaviour of ERK MAPK signalling 30 . The involvement of multiple phosphatases may protect cells from undergoing premature terminal differentiation and is consistent with the ability of different external stimuli to trigger differentiation via different intracellular pathways 3 . Furthermore, the upregulation of basal layer markers in the suprabasal epidermal layers on knockdown of pro-commitment phosphatases mimics features of psoriatic lesions in which ERK is known to be upregulated 15 , leading us to speculate that commitment is deregulated in hyperproliferative skin conditions.…”

“… Abstract Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation 1,2 . While progress has been made in characterising the stem and differentiated cell compartments 3 , the transition between the two cell states, termed commitment 4 , is poorly understood. Here we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension for up to 12h.…”

Peptide‐Functionalized Hydrogels Modulate Integrin Expression and Stemness in Adult Human Epidermal Keratinocytes

“…Human epidermis, the most superficial layer of the skin, is a multilayered epithelium maintained through the proliferation and differentiation of stem cells . A variety of intrinsic and extrinsic factors including extracellular matrix (ECM) composition, physical forces, and neighboring cells control the balance between self‐renewal and differentiation of epidermal stem cells in both heathy and healing skin .…”

Eccrine sweat gland regeneration: still a story of ‘blood, toil, tears and sweat’

“…The regeneration of eSG in skin substitutes could theoretically be achieved by two different approaches: (i) basal keratinocytes can be induced to recapitulate the embryonal development of eSG by being exposed to a correct sequence of signal molecules and the correct microenvironment . Or, (ii) stem cells isolated from eSG (or transdifferentiated from mesenchymal stem cells) can regenerate a gland by wound‐healing mechanisms …”

“…reflects the in vivo situation in humans. The apparent discrepancy demonstrates the crucial role of the microenvironment in which the cells reside.…”