Coulombe Patrick, Tomellini Elisa, Chagraoui Jalila, Mayotte Nadine, Sauvageau Guy
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada.
Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.
Nat Commun. 2025 Jan 2;16(1):195. doi: 10.1038/s41467-024-55225-7.
Ex vivo expansion of hematopoietic stem cells (HSC) requires the maintenance of a stemness state while cells are proliferating. This can be achieved via exposure to UM171 which leads to the degradation of chromatin modifiers and prevents the loss of key epigenetic marks. However, the chromatin landscape varies across populations within the hematopoietic system and the effect of UM171 on self-renewal and differentiation potential of different hematopoietic progenitor cells is less characterized. To address this, we use the CellTag barcoding approach to track the fate of individual stem and progenitor cells during in vitro expansion. We show that, in addition to its HSC self-renewing property, UM171 specifically modulates cell fate of a precursor common to erythroid, megakaryocytic, and mast cells in favor of self-renewal and a mast-bias differentiation trajectory. This differentiation bias can be driven by pro-inflammatory signaling pathways that are activated downstream of UM171 and results in an abundant mast cell population that can be transplanted as part of the graft to populate mice tissues in xenotransplantation studies.
造血干细胞（HSC）的体外扩增需要在细胞增殖时维持干性状态。这可以通过暴露于UM171来实现，UM171会导致染色质修饰因子降解，并防止关键表观遗传标记的丢失。然而，造血系统中不同群体的染色质格局各不相同，UM171对不同造血祖细胞自我更新和分化潜能的影响尚未得到充分表征。为了解决这个问题，我们使用细胞标签条形码方法来追踪体外扩增过程中单个干细胞和祖细胞的命运。我们发现，除了具有造血干细胞自我更新特性外，UM171还特异性地调节红系、巨核细胞和肥大细胞共有的一种前体细胞的细胞命运，有利于自我更新和肥大细胞偏向的分化轨迹。这种分化偏向可由UM171下游激活的促炎信号通路驱动，从而产生大量肥大细胞群体，在异种移植研究中，这些肥大细胞可作为移植物的一部分进行移植，以植入小鼠组织。
