PLos Genet：制造干细胞时需要考虑来源细胞的位置和年龄

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来源：生物谷 2016-02-29 14:21
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2016年2月29日/生物谷BIOON/--在一项新的研究中，来自美国Lieber脑发育研究所（Lieber Institute for Brain Development, LIBD）的Andrew E. Jaffe博士及其研究小组研究了在个人化医疗领域持续获得关注的几种人细胞的分子差异，他们的研究结果于2016年2月25日发表在PLoS Genetics期刊上，论文标题为“Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age”。这项研究提示着用于产生新组织和器官的人类细胞来源可能是进行个人化医疗时的一个重要的考虑因素。2 F* f/ J$ w* A6 j$ M3 S2 {; Y

0 F+ v  }( M! t在全世界，人们正在将大量的资金投资于个人化医疗，重点投入开发用于产生新组织和器官的干细胞系。专家们主要依赖皮肤样品作为他们的细胞来源，这是因为皮肤细胞能够在体外培养中生长，而且在实验室中也相对容易获取它们和将它们重编程为诱导性多能干细胞（iPSCs）。随着发展势头和投资持续，Jaffe博士和及其研究小组发现当产生 病人特异性的干细胞系时，病人细胞样品的来源位置和年龄是重要的考虑因素。
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: p" X% F* ]. \' x. J. b/ R/ L( ~产生病人特异性的干细胞的最为常用的细胞是源自皮肤的细胞，而且它们潜在地接受了最高的环境暴露。LIBD研究人员比较了来自死后大脑硬脑膜（dura mater）的成纤维细胞和来自同一些人皮肤样品的成纤维细胞。尽管这些细胞在显微镜看起来是相同的，但是这项研究鉴定出广泛的表观遗传差异和基因表达差异，这提示着这些细胞对它们在体内的原始位置保持着强大的表观遗传记忆。此外，研究人员发现这些细胞的原始位置也与供者的年龄显著相关联。Jaffe博士注意到，“据我们所知，这是首次证实由这些原始的细胞经过多次细胞分裂产生的纯细胞群体发生显著性的年龄相关变化。”% C/ d; B* n$ V7 O% l- L& Z

: E1 ?& ^# K8 R7 G- x6 \  t这项研究的结果证实来自硬脑膜的和来自皮肤样品的成纤维细胞在一生当中存在显著的差异。随着个人化医疗持续发展，这一发现进一步证实还需研究用于再生新组织和器官的干细胞的表观遗传模式。另外，当制造iPSCs时，还需进一步研究确定需要培养哪些细胞和何时培养它们，以便确认实际上有多少表观遗传记忆被清除。
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doi:10.1371/journal.pgen.1005819
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Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age; A* G9 A% t' Q: }

6 ^* q  A# E9 @- CNikolay A. Ivanov, Ran Tao, Joshua G. Chenoweth, Anna Brandtjen, Michelle I. Mighdoll, John D. Genova, Ronald D. McKay, Yankai Jia, Daniel R. Weinberger, Joel E. Kleinman, Thomas M. Hyde, Andrew E. Jaffe: `/ p2 V$ N2 O3 e4 _& b
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Differentiating pluripotent cells from fibroblast progenitors is a potentially transformative tool in personalized medicine. We previously identified relatively greater success culturing dura-derived fibroblasts than scalp-derived fibroblasts from postmortem tissue. We hypothesized that these differences in culture success were related to epigenetic differences between the cultured fibroblasts by sampling location, and therefore generated genome-wide DNA methylation and transcriptome data on 11 intrinsically matched pairs of dural and scalp fibroblasts from donors across the lifespan (infant to 85 years). While these cultured fibroblasts were several generations removed from the primary tissue and morphologically indistinguishable, we found widespread epigenetic differences by sampling location at the single CpG (N = 101,989), region (N = 697), “block” (N = 243), and global spatial scales suggesting a strong epigenetic memory of original fibroblast location. Furthermore, many of these epigenetic differences manifested in the transcriptome, particularly at the region-level. We further identified 7,265 CpGs and 11 regions showing significant epigenetic memory related to the age of the donor, as well as an overall increased epigenetic variability, preferentially in scalp-derived fibroblasts—83% of loci were more variable in scalp, hypothesized to result from cumulative exposure to environmental stimuli in the primary tissue. By integrating publicly available DNA methylation datasets on individual cell populations in blood and brain, we identified significantly increased inter-individual variability in our scalp- and other skin-derived fibroblasts on a similar scale as epigenetic differences between different lineages of blood cells. Lastly, these epigenetic differences did not appear to be driven by somatic mutation—while we identified 64 probable de-novo variants across the 11 subjects, there was no association between mutation burden and age of the donor (p = 0.71). These results depict a strong component of epigenetic memory in cell culture from primary tissue, even after several generations of daughter cells, related to cell state and donor age.
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有道理，这个符合之前发表的一些文献的报道，不同组织提取出的成纤维细胞重编程得到的iPS细胞具有更强的向原始细胞系方向的分化能力。这一方面是优势，因为可以利用这一特性比较好的得到更容易分化或者分化效率更高的iPS，但另一方面，如果考虑到大规模应用，可以考虑异体的iPS细胞，成本会下降一些