Research Article: The PI3K-Akt pathway inhibits senescence and promotes self-renewal of human skin-derived precursors in vitro

Date Published: August , 2011

Publisher: Blackwell Publishing Ltd

Author(s): Shuang Liu, Shu Liu, Xinyue Wang, Jiaxi Zhou, Yujing Cao, Fei Wang, Enkui Duan.


Skin-derived precursors (SKPs) are embryonic neural crest- or somite-derived multipotent progenitor cells with properties of dermal stem cells. Although a large number of studies deal with their differentiation ability and potential applications in tissue damage repair, only a few studies have concentrated on the regulation of SKP self-renewal. Here, we found that after separation from their physiological microenvironment, human foreskin-derived SKPs (hSKPs) quickly senesced and lost their self-renewal ability. We observed a sharp decrease in Akt activity during this process, suggesting a possible role of the PI3K-Akt pathway in hSKP maintenance in vitro. Blocking this pathway with several inhibitors inhibited hSKP proliferation and sphere formation and increased hSKP senescence. In contrast, activating this pathway with PDGF-AA and a PTEN inhibitor, bpV(pic), promoted proliferation, improved sphere formation, and alleviated senescence of hSKPs, without altering their differentiation potential. Data also implied that this effect was associated with altered actions of FoxO3 and GSK-3β. Our results suggest an important role of the PI3K-Akt pathway in the senescence and self-renewal of hSKPs. These findings also provide a better understanding of the cellular mechanisms underlying hSKP self-renewal and stem cell senescence to allow more efficient expansion of hSKPs for regenerative medical applications.

Partial Text

Among various adult stem cell types within the skin, the newly identified skin-derived precursors (SKPs) have been extensively investigated in recent years because of their multipotent differentiation ability and potential clinical applications. SKPs could differentiate into neurons, glial cells, adipocytes, muscular cell types, insulin-producing cells, and so forth (Qiu et al., 2010; Toma et al., 2001; Guo et al., 2009). Studies also pointed out that murine facial SKPs originated from embryonic neural crest, and dorsal trunk SKPs originated from the somites. SKPs persist into adulthood, with dermal papillae (DP) of hair follicles as one niche for them (Fernandes et al., 2004; Hunt et al., 2008; Jinno et al., 2010). It has recently been shown that SKPs exhibit properties of dermal stem cells that contribute to dermal maintenance, wound healing, and hair follicle morphogenesis (Biernaskie et al., 2009). Therefore, SKPs have great potential in skin and hair follicle reconstitution, and as a donor cell type for the repair of many other tissues. Realizing the therapeutic potential of SKPs in human requires strategies to generate not only a particular functional cell type, but also a considerable cell quantity for transplantation. However, although SKPs have been successfully isolated from human skin (Toma et al., 2005), some fundamental questions remain intangible, especially those concerning their self-renewal regulation. Previously, we found that human foreskin-derived SKPs (hSKPs for short in this article) could not maintain long-term self-renewal in the commonly used suspension culture system, consistent with the report by Gago et al. (2009).

Although SKPs have received intensive attention from researchers in recent years, only a few studies focused on human SKP regulation and in-vitro culture even though some groups did notice that the widely used culture condition could not support a long time expansion of human SKPs (Joannides et al., 2004; Gago et al., 2009). Considering the potential use of hSKPs, a potential dermal stem cell type which could easily be derived from foreskins and other skin biopsies, insights into self-renewal control of human SKPs is important. In this study, we addressed several basic questions.