title: Diabetes impairs hematopoietic stem cell mobilization by altering niche function.
abstract: Success with transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) in patients depends on adequate collection of these cells after mobilization from the bone marrow niche by the cytokine granulocyte colony-stimulating factor (G-CSF). However, some patients fail to achieve sufficient HSPC mobilization. Retrospective analysis of bone marrow transplant patient records revealed that diabetes correlated with poor mobilization of CD34+ HSPCs. In mouse models of type 1 and type 2 diabetes (streptozotocin-induced and db/db mice, respectively), we found impaired egress of murine HSPCs from the bone marrow after G-CSF treatment. Furthermore, HSPCs were aberrantly localized in the marrow niche of the diabetic mice, and abnormalities in the number and function of sympathetic nerve termini were associated with this mislocalization. Aberrant responses to β-adrenergic stimulation of the bone marrow included an inability of marrow mesenchymal stem cells expressing the marker nestin to down-modulate the chemokine CXCL12 in response to G-CSF treatment (mesenchymal stem cells are reported to be critical for HSPC mobilization). The HSPC mobilization defect was rescued by direct pharmacological inhibition of the interaction of CXCL12 with its receptor CXCR4 using the drug AMD3100. These data suggest that there are diabetes-induced changes in bone marrow physiology and microanatomy and point to a potential intervention to overcome poor HSPC mobilization in diabetic patients.
authors: Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Francesca
authors: F
authors: Ferraro
authors: Stefania
authors: S
authors: Lymperi
authors: Simón
authors: S
authors: Méndez-Ferrer
authors: Borja
authors: B
authors: Saez
authors: Joel A
authors: JA
authors: Spencer
authors: Beow Y
authors: BY
authors: Yeap
authors: Elena
authors: E
authors: Masselli
authors: Gallia
authors: G
authors: Graiani
authors: Lucia
authors: L
authors: Prezioso
authors: Elisa Lodi
authors: EL
authors: Rizzini
authors: Marcellina
authors: M
authors: Mangoni
authors: Vittorio
authors: V
authors: Rizzoli
authors: Stephen M
authors: SM
authors: Sykes
authors: Charles P
authors: CP
authors: Lin
authors: Paul S
authors: PS
authors: Frenette
authors: Federico
authors: F
authors: Quaini
authors: David T
authors: DT
authors: Scadden
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement; D002469:Cell Separation / Q000379:methods; D054377:Chemokine CXCL12 / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D033581:Stem Cell Transplantation / Q000379:methods
chemical_list: D018952:Antigens, CD34; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016179:Granulocyte Colony-Stimulating Factor