成体皮肤干细胞的研究对于治疗烧伤、糖尿病引起的皮肤溃疡、皮肤衰老以及构建人类组织工程皮肤都具有重要意义。目前，应用皮肤干细胞进行组织工程学皮肤构建以及皮肤疾病的治疗尚处于初始阶段，但与此同时，临床对于成体皮肤干细胞应用的需求却十分迫切。不同种类的皮肤干细胞在体外的自我更新以及分化能力的提高是目前急需解决的关键科学问题。
8月出版的《衰老细胞》（Aging Cell）发表了中科院动物研究所段恩奎研究员领导的胚胎生物学研究组最新完成的一项研究成果。研究人员发现，真皮来源的干细胞在环境改变的情况下将发生细胞衰老（cellular senescence）现象，并且这种现象最终将导致真皮干细胞自我更新能力的丧失。不同年龄的真皮干细胞对这种细胞衰老的过程具有不同的抵抗能力。
该研究组的一系列实验表明，真皮干细胞的衰老与PI3K-Akt信号通路具有密切的关系：应用LY294002及Akt inhibitor VIII抑制该信号通路，能够迅速促使真皮干细胞进入细胞衰老状态；与之相反，加入PDGF-AA以及bpv(pic)激活该通路则能够有效地抑制真皮干细胞的衰老，促进其自我更新，并且不会影响该细胞的分化能力。
该研究不仅为探索人类皮肤衰老的细胞分子机制奠定了基础，并且为今后应用成体皮肤干细胞进行组织工程皮肤的构建以及应用再生医学与转化医学进行皮肤相关疾病的治疗提供了理论依据与技术支持。该研究得到了中国科学院战略性先导科技专项与国家“发育与生殖研究”重大科学研究计划等基金的资助。该论文共同第一作者是助理研究员刘爽博士和博士生刘恕。(生物谷 Bioon.com)
doi: 10.1111/j.1474-9726.2011.00704.x
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The PI3K‐Akt pathway inhibits senescence and promotes self‐\renewal of human skin‐derived precursors in vitro
Liu, Shuang; Liu, Shu; Wang, Xinyue; Zhou, Jiaxi; Cao, Yujing; Wang, Fei; Duan, Enkui
Keywords:skin‐derived precursors;PI3K‐Akt;self‐\renewal;cellular senescence;adult stem cells;PTENSummarySkin‐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.
