馬峰教授研究團(tuán)隊(duì)近期發(fā)表《Stem Cell Reports》在線文章

近日，Stem Cell Reports在線刊登了我所馬峰教授團(tuán)隊(duì)關(guān)于人類多潛能干細(xì)胞（hPSC）來(lái)源早期成體型紅細(xì)胞獨(dú)特發(fā)育過(guò)程的研究成果。這項(xiàng)工作由實(shí)驗(yàn)血液學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室周家喜教授和日本京都大學(xué)iPS細(xì)胞研究與應(yīng)用中心（CiRA）T.Nakahata教授聯(lián)合署名發(fā)表。
第一作者毛斌博士經(jīng)過(guò)大量研究，運(yùn)用高效的hPSC與成體造血微環(huán)境基質(zhì)細(xì)胞(AGM-S3)共培養(yǎng)向造血細(xì)胞誘導(dǎo)分化的體系，論證了在CD34⁺CD43⁺CD45⁺造血干祖細(xì)胞（HPSC）產(chǎn)生以前已有相當(dāng)量的紅細(xì)胞產(chǎn)生。通過(guò)觀察特定的表型分子（CD34，GPA和CD36等）表達(dá)譜系，可以追蹤這些早期紅細(xì)胞的分化和成熟過(guò)程。研究證實(shí)了該實(shí)驗(yàn)體系誘導(dǎo)產(chǎn)生的早期紅細(xì)胞既有成體造血特性（高表達(dá)β-globin）又兼有內(nèi)皮細(xì)胞特性。
目前，眾多科學(xué)家致力于將hPSC體外誘導(dǎo)分化產(chǎn)生血細(xì)胞以期廣泛應(yīng)用于臨床。已有利用成體造血干細(xì)胞（如臍血CD34⁺細(xì)胞）體外誘導(dǎo)產(chǎn)生成熟紅細(xì)胞并試用于活體的報(bào)道（MC Giarratana et al., 2011）。但由于來(lái)源限制、體外規(guī)模化擴(kuò)增困難以及供者個(gè)體差異等原因，通過(guò)成體造血干細(xì)胞在體外擴(kuò)增大規(guī)模制備標(biāo)準(zhǔn)化的紅細(xì)胞產(chǎn)品而用于輸血替代治療仍是懸而未決的難題。
hPSC具有體外無(wú)限增殖、自我更新和多向分化潛能，有望作為潛在的體外產(chǎn)生紅細(xì)胞的無(wú)限來(lái)源而開(kāi)發(fā)應(yīng)用研究。2008年馬峰教授（F Ma et al., 2008, PNAS）和盧世江教授（SJ Lu et al., 2008, BLOOD）分別報(bào)道了體外成功將hESC誘導(dǎo)分化產(chǎn)生大量功能成熟紅細(xì)胞的方法，但目前仍存在分化增殖和脫核效率較低等問(wèn)題，制約其向臨床應(yīng)用的轉(zhuǎn)化。近年來(lái)該研究領(lǐng)域也未有明顯的突破。究其原因，我們對(duì)hPSC體外向紅細(xì)胞誘導(dǎo)分化的關(guān)鍵調(diào)控機(jī)制尚未明了。本研究發(fā)現(xiàn)與成體造血干細(xì)胞分化紅細(xì)胞不同，hPSC體外向紅細(xì)胞誘導(dǎo)分化存在獨(dú)特的更精密復(fù)雜的早期調(diào)控發(fā)育過(guò)程。通過(guò)探尋hPSC來(lái)源紅細(xì)胞定向分化、擴(kuò)增、成熟的關(guān)鍵調(diào)控因子（包括基因、小分子物質(zhì)等），可以從根本上解決其臨床應(yīng)用的技術(shù)瓶頸。本文的發(fā)表有望引領(lǐng)并推動(dòng)對(duì)hPSC來(lái)源紅細(xì)胞發(fā)育機(jī)制的研究。
本研究成果的另一重要意義在于發(fā)現(xiàn)hPSC來(lái)源的早期成體特性紅細(xì)胞兼有內(nèi)皮細(xì)胞特性，提示可以通過(guò)基因工程技術(shù)建立具有內(nèi)皮特性的永生化紅系祖細(xì)胞株。這可能對(duì)先天性紅細(xì)胞增生低下性疾病、鐮狀紅細(xì)胞貧血、地中海貧血等紅細(xì)胞發(fā)育異?；颊咛峁┤碌闹委熌Ｊ?。目前，進(jìn)一步深入的工作正在積極有序推進(jìn)中。
 
Early Development of Definitive Erythroblasts from Human Pluripotent Stem Cells Defined by Expression of Glycophorin A/CD235a, CD34, and CD36
Bin Mao, Shu Huang, Xulin Lu, Wencui Sun, Ya Zhou, Xu Pan, Jinfeng Yu, Mowen Lai, Bo Chen, Qiongxiu Zhou, Song Mao,Guohui Bian, Jiaxi Zhou, Tatsutoshi Nakahata, Feng Ma* (*corresponding)
<Summary>
The development of human erythroid cells has been mostly examined in models of adult hematopoiesis while their early derivation during embryonic and fetal stages is largely unknown. We observed the development and maturation of erythroblasts derived from human pluripotent stem cell (hPSCs) by an efficient co-culture system. These hPSC-derived early erythroblasts initially showed definitive characteristics with a glycophorin A⁺ (GPA⁺) CD34^lowCD36^- phenotype and were distinct from adult CD34⁺ cell-derived ones. After losing CD34 expression,  early GPA⁺CD36^- erythroblasts matured into GPA⁺CD36^low/+ stage as the latter expressed higher levels of β-globin along with a gradual loss of mesodermal and endothelial properties, and terminally suppressed CD36. We establish a unique in vitro model to trace the early development of hPSC-derived erythroblasts by serial expression of CD34, GPA and CD36. Our findings may provide insight into understanding of human early erythropoiesis and ultimately therapeutic potential. (DOI: http://dx.doi.org/10.1016/j.stemcr.2016.09.002)
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