Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.
Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.
复制标题
DOI：
10.1002/stem.2100
复制
发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Pang Q
中科院分区：
文献类型：
--
作者：
Amarachintha S;Sertorio M;Wilson A;Li X;Pang Q
范可尼贫血（FA）患者发生骨髓（BM）衰竭或白血病。造血干细胞移植是治疗这些毁灭性并发症的一种标准疗法。我们确定了一组间充质基质细胞（MSC）衍生的代谢产物，甘油磷脂及其内源性抑制剂，5-（十四烷氧基）-2-糠酸（TOFA），作为供体造血干细胞和祖细胞（HSPCs）的调节剂。我们提供了两个证据证明TOFA可以改善FA MSCs的造血支持功能：（1）有限稀释CAFC试验显示，与未处理的共培养物相比，TOFA显著增加了Fanca−/−或Fancd 2 −/−共培养物中的鹅卵石集落。(2)使用从共培养物中收集的输出细胞进行的竞争性再增殖试验表明，TOFA极大地减轻了移植有来自Fanca−/−或Fancd 2 −/−共培养物的细胞的受体小鼠的外周血和BM中供体髓样（CD 45.2 + Gr 1 + Mac 1+）隔室的异常扩增。此外，机制研究确定Tlr 4信号传导为介导甘油磷脂作用的负责途径。因此，在FA MSC中靶向甘油磷脂生物合成可能是改善造血和干细胞移植的治疗策略。
Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids and their endogenous inhibitor, 5-(Tetradecyloxy)-2-furoic acid (TOFA), as regulators of donor hematopoietic stem and progenitor cells (HSPCs). We provided two pieces of evidence that TOFA could improve hematopoiesis-supporting function of FA MSCs: (1) limiting-dilution CAFC assay revealed that TOFA significantly increased cobblestone colonies in Fanca−/− or Fancd2−/− co-cultures compared to untreated co-cultures. (2) Competitive repopulating assay using output cells collected from co-cultures showed that TOFA greatly alleviated the abnormal expansion of the donor myeloid (CD45.2+Gr1+Mac1+) compartment in both peripheral blood and BM of recipient mice transplanted with cells from Fanca−/− or Fancd2−/− co-cultures. Further, mechanistic studies identified Tlr4 signaling as the responsible pathway mediating the effect of glycerophospholipids. Thus, targeting Glycerophospholipid biosynthesis in FA MSCs could be a therapeutic strategy to improve hematopoiesis and stem cell transplantation.