ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition

Abstract

Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes.

Small molecule drugs promote repopulation of transplanted hepatocytes by stimulating cell dedifferentiation

“…However, ROCK inhibitors have now been recognized as useful tools to promote the survival of multiple types of stem cells. 39 …”

MicroRNA-148a Controls Epidermal and Hair Follicle Stem/Progenitor Cells by Modulating the Activities of ROCK1 and ELF5

“…Our findings suggest that negative regulation of Rock1 by miR-148a may maintain the selfrenewal and stemness characteristics of HF-SCs, which has been observed in primary skin tissue cultures after inhibition of Rock1 (An et al, 2018). In addition, studies have suggested that Rock1 signalling inhibition elevates stem/progenitor cell functions, in vitro (Centonze et al, 2022). Furthermore, Rock1 has been shown to promote embryonic SC-colony formation and maintenance of neural progenitor cells (Chang et al, 2010).…”

“…Rock1 has been shown to be involved in proliferation and differentiation processes of keratinocytes and in other epithelial cells (Ma et al, 2017). In addition, reduced Rock1 function results in cellular senescence, both in vitro and in vivo (Centonze et al, 2022;Kümper et al, 2016). This loss of Rock1 mediated cellular senescence involves downregulation of cell cycle protein Cdk1 (Diril et al, 2012).…”

554 MicroRNA-148a controls epidermal and hair follicle stem/progenitor cells by modulating the activities of Rock1 and Elf5

“…Our findings suggest that negative regulation of Rock1 by miR-148a may maintain the self-renewal and stemness characteristics of HF SCs, which have been observed in primary skin tissue cultures after inhibition of ROCK1 (An et al, 2018). In addition, studies have suggested that ROCK1 signaling inhibition elevates stem/progenitor cell functions, in vitro (Centonze et al, 2022). Furthermore, ROCK1 has been shown to promote embryonic SC colony formation and maintenance of neural progenitor cells (Chang et al, 2010), whereas Elf5 is expressed in differentiated epidermal and oral mouse KCs as well as in the inner root sheath and outer root sheath of HFs (Choi et al, 2008;Oakes et al, 2008;Parikh et al, 2008;Singh et al, 2019;Tummala and Sinha, 2006).…”