小柯机器人

MLLT3调控人造血干细胞的自我更新和移植
2019-11-28 14:31

美国加州大学洛杉矶分校Hanna K. A. Mikkola、Vincenzo Calvanese等研究人员发现MLLT3调控人类造血干细胞的自我更新和移植。该研究2019年11月27日在线发表于国际学术期刊《自然》。

研究人员发现MLLT3(也称为AF9)是HSC的关键调节因子,它在人类胎儿、新生儿和成人HSC中高度丰富,但在培养条件下却被下调。MLLT3的降低阻止了培养的可移植人类造血干细胞或祖细胞(HSPC)的维持,而培养中MLLT3的稳定表达则使可移植HSC的扩增超过了12倍,从而在原代和次代小鼠受体中提供了平衡的多谱系重建。与内源性MLLT3相似,过表达的MLLT3定位于HSPC中的活性启动子,维持H3K79me2的水平并保护培养的HSC转录程序。因此,MLLT3充当HSC维持因子,将组蛋白阅读器和修饰活性联系起来以调节HSC基因表达,并可能为扩大用于移植的HSC提供有希望的方法。

据了解,目前对调控HSC自我更新机制的了解有限,而且其培养失败阻碍了HSC移植的发展。

附:英文原文

Title: MLLT3 governs human haematopoietic stem-cell self-renewal and engraftment

Author: Vincenzo Calvanese, Andrew T. Nguyen, Timothy J. Bolan, Anastasia Vavilina, Trent Su, Lydia K. Lee, Yanling Wang, Fides D. Lay, Mattias Magnusson, Gay M. Crooks, Siavash K. Kurdistani, Hanna K. A. Mikkola

Issue&Volume: 2019-11-27

Abstract: Limited knowledge of the mechanisms that govern the self-renewal of human haematopoietic stem cells (HSCs), and why this fails in culture, have impeded the expansion of HSCs for transplantation1. Here we identify MLLT3 (also known as AF9) as a crucial regulator of HSCs that is highly enriched in human fetal, neonatal and adult HSCs, but downregulated in culture. Depletion of MLLT3 prevented the maintenance of transplantable human haematopoietic stem or progenitor cells (HSPCs) in culture, whereas stabilizing MLLT3 expression in culture enabled more than 12-fold expansion of transplantable HSCs that provided balanced multilineage reconstitution in primary and secondary mouse recipients. Similar to endogenous MLLT3, overexpressed MLLT3 localized to active promoters in HSPCs, sustained levels of H3K79me2 and protected the HSC transcriptional program in culture. MLLT3 thus acts as HSC maintenance factor that links histone reader and modifying activities to modulate HSC gene expression, and may provide a promising approach to expand HSCs for transplantation. MLLT3 is identified as a crucial regulator of the self-renewal of human haematopoietic stem cells, and helps to maintain an active chromatin state in haematopoietic stem-cell regulatory genes during culture.

DOI: 10.1038/s41586-019-1790-2

Source:https://www.nature.com/articles/s41586-019-1790-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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