Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling

Stem Cells. 2015 Nov;33(11):3382-96. doi: 10.1002/stem.2100. Epub 2015 Jul 24.

Abstract

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.

Keywords: Fanconi anemia; Hematopoietic stem cell transplantation; Marrow stromal stem cells; Myeloid cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Fanconi Anemia / genetics
  • Fanconi Anemia Complementation Group A Protein / deficiency*
  • Fanconi Anemia Complementation Group A Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / deficiency*
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Glycerophospholipids / biosynthesis*
  • Hematopoietic Stem Cells / metabolism*
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / physiology
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Fanca protein, mouse
  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group A Protein
  • Fanconi Anemia Complementation Group D2 Protein
  • Glycerophospholipids
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4