Nagaria Pratik K, Robert Carine, Park Tea Soon, Huo Jeffrey S, Zambidis Elias T, Rassool Feyruz V
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Institute for Cell Engineering and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Stem Cells Int. 2016;2016:3826249. doi: 10.1155/2016/3826249. Epub 2016 Sep 1.
Human induced pluripotent stem cells (hiPSCs) are reprogrammed from adult or progenitor somatic cells and must make substantial adaptations to ensure genomic stability in order to become "embryonic stem cell- (ESC-) like." The DNA damage response (DDR) is critical for maintenance of such genomic integrity. Herein, we determined whether cell of origin and reprogramming method influence the DDR of hiPSCs. We demonstrate that hiPSCs derived from cord blood (CB) myeloid progenitors (i.e., CB-iPSC) via an efficient high-fidelity stromal-activated (sa) method closely resembled hESCs in DNA repair gene expression signature and irradiation-induced DDR, relative to hiPSCs generated from CB or fibroblasts via standard methods. Furthermore, sa-CB-iPSCs also more closely resembled hESCs in accuracy of nonhomologous end joining (NHEJ), DNA double-strand break (DSB) repair, and C-MYC transcriptional signatures, relative to standard hiPSCs. Our data suggests that hiPSCs derived via more efficient reprogramming methods possess more hESC-like activated MYC signatures and DDR signaling. Thus, an authentic MYC molecular signature may serve as an important biomarker in characterizing the genomic integrity in hiPSCs.
人诱导多能干细胞（hiPSC）是由成体或祖代体细胞重编程而来，为了变得“类胚胎干细胞（ESC）”，它们必须进行大量适应性改变以确保基因组稳定性。DNA损伤反应（DDR）对于维持这种基因组完整性至关重要。在此，我们确定了细胞来源和重编程方法是否会影响hiPSC的DDR。我们证明，相对于通过标准方法从脐带血（CB）或成纤维细胞产生的hiPSC，通过高效高保真基质激活（sa）方法从脐带血（CB）髓系祖细胞（即CB-iPSC）衍生而来的hiPSC在DNA修复基因表达特征和辐射诱导的DDR方面与hESC非常相似。此外，相对于标准hiPSC，sa-CB-iPSC在非同源末端连接（NHEJ）的准确性、DNA双链断裂（DSB）修复和C-MYC转录特征方面也更接近hESC。我们的数据表明，通过更高效重编程方法衍生的hiPSC具有更多类hESC激活的MYC特征和DDR信号。因此，真实的MYC分子特征可能是表征hiPSC基因组完整性的重要生物标志物。
