美国科学家将实验老鼠的4个遗传因子转化成了成纤维细胞，并由此制造出类似于人体造血干细胞的细胞，这些造血干细胞每天会在人体内制造出数百万个新鲜的血液细胞。

这项研究有助于科学家们未来为血液病症患者量身打造造血干/祖细胞，用于细胞替代疗法中。相关研究发表在6月13日出版的《细胞·干细胞》杂志上。

美国西奈山医院伊坎医学院的研究人员对18个诱导血液形成活动的遗传因子进行了筛查，找出了其中的4个转录因子 Gata2、Gfi1b、cFos、Etv6，并进行了正确的组合，培育出了血管前体细胞以及随后的成纤维细胞。这些前体细胞表达了一个人类的CD34分子（其会选择性地表达于人类及其他哺乳动物的造血干/祖细胞表面，并随细胞的成熟逐渐减弱至消失）、一个Sca1（干细胞抗原-1）以及一个Prominin1（一种造血干细胞和神经干细胞的表面标志物）。

该论文的第一作者、伊坎医学院发育和再生生物学博士研究员卡洛斯·菲利普－佩雷拉表示：“我们在培养皿中培育出来的这些细胞与我们在老鼠的胚胎中发现的细胞在基因表达方面一模一样，最终，我们有望借此制造出成熟的血液细胞。”

伊坎医学院发育和再生生物学教授艾霍尔·雷米斯奇卡表示：“有很多研究人员一直在尝试用胚胎干细胞来培育造血干细胞，但我们另辟蹊径，使用成熟老鼠的成纤维细胞，再加上正确的蛋白质组合取得了成功。”

西奈山医院伊坎医学院院长丹尼斯·查尼表示：“这一发现或许仅仅是一个开始，将有助于我们为血液病患者找到治疗方法。”

佩雷拉说，在血液干细胞移植手术中，获得合适的捐赠一直是个大问题。捐赠者必须满足罹患白血病（血癌）、再生障碍性贫血、淋巴瘤、多发性骨髓瘤以及免疫系统缺陷等病症的病患的需要。佩雷拉表示：“培育出造血干细胞是一种非常好的替代方法。”

该研究的另一名作者、伊坎医学院发育和再生生物学副教授凯特瑞·摩尔表示：“我们能在一个培养皿中培育出如此多的成血细胞真是一件令人兴奋的事情。希望新方法应用于人体细胞可以取得同样的成功。”

Researchers Succeed in Programming Blood Forming Stem Cells

By transferring four genes into mouse fibroblast cells,researchers at the Icahn School of Medicine at Mount Sinai have produced cells that resemble hematopoietic stem cells,which produce millions of new blood cells in the human body every day.These findings provide a platform for future development of patient-specific stem/progenitor cells,and more differentiated blood products,for cell-replacement therapy.

The study,titled,“Induction of a Hemogenic Program in Mouse Fibroblasts,”was published online in CELL STEM CELL on June 13.Mount Sinai researchers screened a panel of 18 genetic factors for inducing blood-forming activity and identified a combination of four transcription factors,Gata2,Gfi1b,cFos,and Etv6 as sufficient to generate blood vessel precursor cells with the subsequent appearance of hematopoietic cells.The precursor cells express a human CD34 reporter,Sca1 and Prominin1 within a global endothelial transcription program.

“The cells that we grew in a petri dish are identical in gene expression to those found in the mouse embryo and could eventually generate colonies of mature blood cells,”said the first author of the study,Carlos Filipe Pereira,PhD,Postdoctoral Fellow of Developmental and Regenerative Biology at the Icahn School of Medicine.Other leaders of the research team that screened the genetic factors to find the right combination included Kateri Moore,DVM,Associate Professor of Developmental and Regenerative Biology at the Icahn School and Ihor R.Lemischka,PhD,Professor of Developmental and Regenerative Biology,Pharmacology and Systems Therapeutics and Director of The Black Family Stem Cell Institute at The Mount Sinai Medical Center.

“The combination of gene factors that we used was not composed entirely of the most obvious or expected proteins,”said Dr.Lemischka.“Many investigators have been trying to grow hematopoietic stem cells from embryonic stem cells,but this process has been problematic.Instead,we used mature mouse fibroblasts,picked the right combination of proteins,and it worked.”

“This discovery is just the beginning of something new and exciting and can hopefully be used to identify a treatment for blood disorders,”said Dennis S.Charney,MD,Anne and Joel Ehrenkranz Dean of the Icahn School of Medicine at Mount Sinai and Executive Vice President for Academic Affairs at The Mount Sinai Medical Center.

According to Dr.Pereira,there is a critical shortage of suitable donors for blood stem cell transplants.Donors are currently necessary to meet the needs of patients suffering from blood diseases such as leukemia,aplastic anemia,lymphomas,multiple myeloma and immune deficiency disorders.“Programming of hematopoietic stem cells represents an exciting alternative,”said Pereira.

“Dr.Lemischka and I have been working together for over 20 years in the fields of hematopoiesis and stem cell biology,”said Dr.Moore,senior author of the study.“It is truly exciting to be able to grow these blood forming cells in a culture dish and learn so much from them.We have already started applying this new approach to human cells and anticipate similar success.”

Mount Sinai Innovation Partners is managing the intellectual property for this cellreplacement technology on behalf of the Mount Sinai researchers and is actively engaged with commercial collaboration opportunities.

Summary

Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition.We attempted to induce this process in mouse fibroblasts by screening a panel of factors for hemogenic activity.We identified a combination of four transcription factors,Gata2,Gfi1b,cFos,and Etv6,that efficiently induces endothelial-like precursor cells,with the subsequent appearance of hematopoietic cells.The precursor cells express a human CD34 reporter,Sca1,and Prominin1 within a global endothelial transcription program.Emergent hematopoietic cells possess nascent hematopoietic stem cell gene-expression profiles and cell-surface phenotypes.After transgene silencing and reaggregation culture,the specified cells generate hematopoietic colonies in vitro.