Open AccessFanconi Anemia Mesenchymal Stromal Cells‐Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll‐Like Receptor Signaling
Author(s) -
Amarachintha Surya,
Sertorio Mathieu,
Wilson Andrew,
Li Xiaoli,
Pang Qishen
Publication year - 2015
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2100
Subject(s) - biology , stem cell , fanconi anemia , mesenchymal stem cell , haematopoiesis , fancd2 , bone marrow , cancer research , microbiology and biotechnology , transplantation , progenitor cell , fanca , cd34 , hematopoietic stem cell , immunology , medicine , dna repair , biochemistry , gene
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. We provided two pieces of evidence that TOFA could improve hematopoiesis‐supporting function of FA MSCs: (a) limiting‐dilution cobblestone area‐forming cell assay revealed that TOFA significantly increased cobblestone colonies in Fanca−/− or Fancd2−/− cocultures compared to untreated cocultures. (b) Competitive repopulating assay using output cells collected from cocultures 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−/− cocultures. Furthermore, 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. S tem C ells 2015;33:3382–3396