title: A novel role of BMP4 in adult hematopoietic stem and progenitor cell homing via Smad independent regulation of integrin-α4 expression.
abstract: Although it is well established that BMP4 plays an important role in the development of hematopoietic system, it is less well understood whether BMP4 affects adult hematopoiesis and how. Here, we describe a novel mechanism by which BMP4 regulates homing of murine as well as human hematopoietic stem/progenitor cells (HSPCs). BMP4 treatment of murine BM derived c-kitLin-Sca-1 (KLS) and CD150CD48-KLS cells for up to 5 days in vitro prevented the culture-induced loss of Integrin-α4 (ITGA4) expression as well as homing. The effect on ITGA4 expression in response to BMP4 is mediated via SMAD-independent phosphorylation of p38 MAPK, which activates microphthalmia-associated transcription factor (MITF), known to induce ITGA4 expression. Elevated ITGA4 expression significantly enhanced HSPC attachment to bone marrow stromal cells, homing and long-term engraftment of the BMP4 treated cells compared with the cells cultured without BMP4. BMP4 also induced expression of ITGA4 on human BM derived Lin-CD34 cells in culture, which was associated with improved homing potential. Thus, BMP4 prevents culture-induced loss of ITGA4 expression on HSPCs in a SMAD-independent manner, resulting in improved homing of cultured HSPCs and subsequent hematopoietic reconstitution.
  
  
  CONCLUSIONS
  Cytokine-induced loss of murine as well as human HSPC homing during ex vivo culture can be prevented by addition of BMP4. In HSPCs, BMP4 directly regulates Integrin-α4 expression through SMAD-independent p38 MAPK-mediated signaling.
authors.affiliation: Interdepartmental Stem Cell Institute, KU Leuven, Herestraat 49, Leuven, Belgium. satish.khurana@med.kuleuven.be
authors.forename: Satish
authors.initials: S
authors.lastname: Khurana
authors.forename: Shannon
authors.initials: S
authors.lastname: Buckley
authors.forename: Sarah
authors.initials: S
authors.lastname: Schouteden
authors.forename: Stephen
authors.initials: S
authors.lastname: Ekker
authors.forename: Anna
authors.initials: A
authors.lastname: Petryk
authors.forename: Michel
authors.initials: M
authors.lastname: Delforge
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Verfaillie
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D039441:Integrin alpha4 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D051785:Smad Proteins; D039441:Integrin alpha4; D048051:p38 Mitogen-Activated Protein Kinases