近日，美国哥伦比亚大学教授Lei Ding团队发现，造血干细胞生态位的产生和维持是通过一个表观转录组程序来区分的。相关论文于2024年4月23日发表在《细胞》杂志上。

据悉，生态位通常被认为是一个预先建立的维持干细胞的结构。因此，其形成的规律在很大程度上仍未被探索。是否有不同的分子机制控制干细胞生态位的建立和维持尚不清楚。

为了解决这个问题，研究人员比较了围产期和成人骨髓间充质间质细胞(MSCs)，这是造血干细胞(HSC)生态位的关键组成部分。MSCs在围产期表现出介导m⁶A mRNA甲基化基因的富集，并在出生后不久下调m⁶A 甲基转移酶Mettl3的表达。

从发育中的MSCs而不是成骨细胞中缺失Mettl3会导致，过度的成骨分化和严重的造血干细胞生态位形成缺陷，这可以通过m⁶A 靶点Klf2的缺失得到显著挽救。相比之下，出生后MSCs中Mettl3的缺失对造血干细胞生态位没有影响。干细胞生态位的产生和维持依赖于不同的分子机制，这可能被用于再生医学。

附：英文原文

Title: Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program

Author: Longfei Gao, Heather Lee, Joshua H. Goodman, Lei Ding

Issue&Volume: 2024-04-23

Abstract: The niche is typically considered as a pre-established structure sustaining stem cells.Therefore, the regulation of its formation remains largely unexplored. Whether distinctmolecular mechanisms control the establishment versus maintenance of a stem cell nicheis unknown. To address this, we compared perinatal and adult bone marrow mesenchymalstromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche.MSCs exhibited enrichment in genes mediating m6A mRNA methylation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs but not osteoblasts led to excessive osteogenic differentiationand a severe HSC niche formation defect, which was significantly rescued by deletionof Klf2, an m6A target. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche. Stem cell niche generation and maintenancethus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

DOI: 10.1016/j.cell.2024.03.032

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00348-9