Science2014-06-16 2:19 PM

上皮干细胞的可塑性 Plasticity of epithelial stem cells in tissue regeneration

论文摘要 

在日常生活中,我们的身体不断经受着考验:细胞暴露于外部环境中,接受刺激发生剥离,比如我们的皮肤在风吹日晒中受到损耗。尽管我们没有看到这一过程,但是细胞确实定期发生了更换,并且这也是身体必需的一个过程。

干细胞是这一过程的主导者,每个上皮细胞通过其自身独特的微环境,分化成组织所需的特殊细胞。来自霍德华休斯医学院,洛克菲勒大学的两位学者就这一内容进行了综述介绍,他们探讨了不同类型的干细胞如何保持其可塑性和可逆性,还有如何重新获得长期的自我更新能力,此外作者还讨论了细胞可塑性对再生医学和癌症的影响。

干细胞是一类特殊的细胞,由于有潜力生成一些具有特定功能的特化细胞,干细胞在医学应用领域具有重要的价值。干细胞生成这些分化细胞的能力对于机体的正常维持、生长及修复至关重要。

科学家们一直希望能破解干细胞如何分化,以及什么指挥其分化的奥秘,近期一组研究人员发现了一类特殊的过度细胞:过渡扩充细胞(Transit-Amplifying Cell,TACs)。许多类型的哺乳动物干细胞都生成TACs,TACs是干细胞和其最终产物:血液、皮肤和别处完全分化的细胞之间的一种中间体。在过去,人们将TACs视作是坐等被动生成组织的一群细胞。没有人会想到它们起着调控作用。

5月的一项研究通过敲除成年小鼠毛囊中的负责基因使得TACs无法生成Sonic Hedgehog蛋白。由此,毛囊干细胞和它们TACs的增殖均受到了影响。研究人员进一步证实静息干细胞群增殖需要Sonic Hedgehog。TACs是许多不同的干细胞谱系的一个阶段,研究人员断定尽管精确的机制有可能有所差异,在我们的血液和肠等其他组织中TACs有可能发挥了相似的作用。

另外,今年2月,来自来自澳大利亚的科学家们发现乳腺干细胞和它们的被称作祖细胞的子细胞具有比人们之前所认为的更长的寿命,并且在青春期和一生当中都是有活性的。这项研究应当解决了这个科学领域中一个一直存在的争论,这是因为它证实乳腺干细胞确实是真正的能够自我更新的干细胞,能够产生乳腺中的所有细胞。

这是乳腺干细胞的研究成果,肠腺研究方面,一组研究人员对小鼠小肠肠腺中侧向抑制(lateral inhibition)和线性弹性的机制进行了活体研究。他们发现,肠腺细胞维持一个容许性的染色质状态——在该状态下一个转录因子来决定形成哪个细胞系,这一点是侧向抑制的基础。

这些都是值得关注的研究新成果,但是还有许多研究方面依然有待探讨,如干细胞如何保持其可塑性和可逆性,干细胞重编程等等。

Abstract 

Tissues rely upon stem cells for homeostasis and repair. Recent studies show that the fate and multilineage potential of epithelial stem cells can change depending on whether a stem cell exists within its resident niche and responds to normal tissue homeostasis, whether it is mobilized to repair a wound, or whether it is taken from its niche and challenged to de novo tissue morphogenesis after transplantation. In this Review, we discuss how different populations of naturally lineage-restricted stem cells and committed progenitors can display remarkable plasticity and reversibility and reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. We also discuss the implications of cellular plasticity for regenerative medicine and for cancer.

Structured Abstract

Background
At the surface of body organs, epithelial tissues must withstand harsh external environments. To do so, they rely heavily upon stem cells to replenish and repair wounds and replace the many cells that die from this wear and tear. To maintain tissue size, the number of cells lost must be compensated by cell divisions. Tissue homeostasis and wound-repair are ensured by stem cells, located within specialized microenvironments, referred to as niches. Each niche is tailored to accommodate the regenerative needs of its tissue. Some tissues—for instance, skin epithelium—harbor multiple stem cell niches, each with their own responsibility for maintaining cellular balance within their particular domain. Governance of discrete tissue units has ancient origins and is also seen in Drosophila gut epithelium.

Identifying stem cells and tracking their progeny is accelerated by lineage tracing, a technique in which a stem cell is genetically marked in its niche and in a way such that their subsequent progeny retain marker expression. Although interpretation of these experiments has been complicated by the lack of specificity of most stem cell markers, this method can be helpful in evaluating the contribution of stem cells to tissue homeostasis and wound-repair. Additional tools include live imaging of marked stem cells and ablating stem cells in situ either by laser or by targeted expression of diphtheria toxin/receptor in stem cells.

Editor's Summary

The versatility of epithelial stem cells

Stem cells are very important in the maintenance of our bodies' tissues and organs. Blanpain and Fuchs review how different populations of naturally lineage-restricted epithelial stem cells and committed progenitors can also display remarkable plasticity. These cells can reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. These abilities depend on whether the stem cell remains within its resident niche or has been mobilized to repair a wound. Such cellular plasticity has implications for regenerative medicine and for cancer.

Science, this issue p. 10.1126/science.1242281
( http://www.sciencemag.org/content/344/6189/1242281 )

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