Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells

  • Blood. 2015 Aug 27;126(9):1086-94. doi: 10.1182/blood-2014-09-598540.
Zahra Kabiri  1 ,  Akihiko Numata  2 ,  Akira Kawasaki  2 ,  Edison  3 ,  Daniel G Tenen  4 ,  David M Virshup  5
Affiliations
  • 1. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry and.
  • 2. Cancer Science Institute, National University of Singapore, Singapore;
  • 3. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore;
  • 4. Cancer Science Institute, National University of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA; and.
  • 5. Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry and Department of Pediatrics, Duke University School of Medicine, Durham, NC.
PMID: 26089398 DOI: 10.1182/blood-2014-09-598540
Abstract

Wnt signaling controls early embryonic hematopoiesis and dysregulated β-catenin is implicated in leukemia. However, the role of Wnts and their source in adult hematopoiesis is still unclear, and is clinically important as upstream Wnt inhibitors enter clinical trials. We blocked Wnt secretion in hematopoietic lineages by targeting Porcn, a membrane-bound O-acyltransferase that is indispensable for the activity and secretion of all vertebrate Wnts. Surprisingly, deletion of Porcn in Rosa-CreER(T2)/Porcn(Del), MX1-Cre/Porcn(Del), and Vav-Cre/Porcn(Del) mice had no effects on proliferation, differentiation, or self-renewal of adult hematopoietic stem cells. Targeting Wnt secretion in the bone marrow niche by treatment with a PORCN inhibitor, C59, similarly had no effect on hematopoiesis. These results exclude a role for hematopoietic PORCN-dependent Wnts in adult hematopoiesis. Clinical use of upstream Wnt inhibitors is not likely to be limited by effects on hematopoiesis.