Lo Celso Cristina, Berta Melanie A, Braun Kristin M, Frye Michaela, Lyle Stephen, Zouboulis Christos C, Watt Fiona M
Massachusetts General Hospital, Center for Regenerative Medicine, Boston, Massachusetts, USA.
Stem Cells. 2008 May;26(5):1241-52. doi: 10.1634/stemcells.2007-0651. Epub 2008 Feb 28.
The current belief is that the epidermal sebaceous gland (SG) is maintained by unipotent stem cells that are replenished by multipotent stem cells in the hair follicle (HF) bulge. However, sebocytes can be induced by c-Myc (Myc) activation in interfollicular epidermis (IFE), suggesting the existence of bipotential stem cells. We found that every SZ95 immortalized human sebocyte that underwent clonal growth in culture generated progeny that differentiated into both sebocytes and cells expressing involucrin and cornifin, markers of IFE and HF inner root sheath differentiation. The ability to generate involucrin positive cells was also observed in a new human sebocyte line, Seb-E6E7. SZ95 xenografts differentiated into SG and IFE but not HF. SZ95 cells that expressed involucrin had reduced Myc levels; however, this did not correlate with increased expression of the Myc repressor Blimp1, and Blimp1 expression did not distinguish cells undergoing SG, IFE, or HF differentiation in vivo. Overexpression of Myc stimulated sebocyte differentiation, whereas overexpression of beta-catenin stimulated involucrin and cornifin expression. In transgenic mice simultaneous activation of Myc and beta-catenin revealed mutual antagonism: Myc blocked ectopic HF formation and beta-catenin reduced SG differentiation. Overexpression of the Myc target gene Indian hedgehog did not promote sebocyte differentiation in culture and cyclopamine treatment, while reducing proliferation, did not block Myc induced sebocyte differentiation in vivo. Our studies provide evidence for a bipotential epidermal stem cell population in an in vitro model of human epidermal lineage selection and highlight the importance of Myc as a regulator of sebocyte differentiation.
目前的观点认为，表皮皮脂腺（SG）由单能干细胞维持，这些单能干细胞由毛囊（HF）隆突中的多能干细胞补充。然而，在毛囊间表皮（IFE）中，c-Myc（Myc）激活可诱导皮脂腺细胞分化，这表明存在双能干细胞。我们发现，在培养中经历克隆生长的每一个SZ95永生化人皮脂腺细胞产生的子代细胞，既能分化为皮脂腺细胞，也能分化为表达兜甲蛋白和角蛋白的细胞，这些是IFE和HF内根鞘分化的标志物。在一种新的人皮脂腺细胞系Seb-E6E7中也观察到了产生兜甲蛋白阳性细胞的能力。SZ95异种移植物分化为SG和IFE，但不分化为HF。表达兜甲蛋白的SZ95细胞Myc水平降低；然而，这与Myc抑制因子Blimp1表达的增加无关，并且Blimp1表达在体内并不能区分正在经历SG、IFE或HF分化的细胞。Myc的过表达刺激皮脂腺细胞分化，而β-连环蛋白的过表达刺激兜甲蛋白和角蛋白的表达。在转基因小鼠中，Myc和β-连环蛋白的同时激活显示出相互拮抗作用：Myc阻断异位HF形成，β-连环蛋白减少SG分化。Myc靶基因印度刺猬蛋白的过表达在培养中并未促进皮脂腺细胞分化，环杷明处理虽减少增殖，但并未在体内阻断Myc诱导的皮脂腺细胞分化。我们的研究为人类表皮谱系选择的体外模型中的双能表皮干细胞群体提供了证据，并强调了Myc作为皮脂腺细胞分化调节因子的重要性。
