title: Stage-specific roles for CXCR4 signaling in murine hematopoietic stem/progenitor cells in the process of bone marrow repopulation.
abstract: Hematopoietic cell transplantation has proven beneficial for various intractable diseases, but it remains unclear how hematopoietic stem/progenitor cells (HSPCs) home to the bone marrow (BM) microenvironment, initiate hematopoietic reconstitution, and maintain life-long hematopoiesis. The use of newly elucidated molecular determinants for overall HSPC engraftment should benefit patients. Here, we report that modification of C-X-C chemokine receptor type 4 (Cxcr4) signaling in murine HSPCs does not significantly affect initial homing/lodging events, but leads to alteration in subsequent BM repopulation kinetics, with observations confirmed by both gain- and loss-of-function approaches. By using C-terminal truncated Cxcr4 as a gain-of-function effector, we demonstrated that signal augmentation likely led to favorable in vivo repopulation of primitive cell populations in BM. These improved features were correlated with enhanced seeding efficiencies in stromal cell cocultures and altered ligand-mediated phosphorylation kinetics of extracellular signal-regulated kinases observed in Cxcr4 signal-augmented HSPCs in vitro. Unexpectedly, however, sustained signal enhancement even with wild-type Cxcr4 overexpression resulted in impaired peripheral blood (PB) reconstitution, most likely by preventing release of donor hematopoietic cells from the marrow environment. We thus conclude that timely regulation of Cxcr4/CXCR4 signaling is key in providing donor HSPCs with enhanced repopulation potential following transplantation, whilst preserving the ability to release HSPC progeny into PB for improved transplantation outcomes.
authors: Division of Stem Cell Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Stem Cell Bank, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors: Chen-Yi
authors: CY
authors: Lai
authors: Satoshi
authors: S
authors: Yamazaki
authors: Motohito
authors: M
authors: Okabe
authors: Sachie
authors: S
authors: Suzuki
authors: Yoshihiro
authors: Y
authors: Maeyama
authors: Yasuaki
authors: Y
authors: Iimura
authors: Masafumi
authors: M
authors: Onodera
authors: Shigeru
authors: S
authors: Kakuta
authors: Yoichiro
authors: Y
authors: Iwakura
authors: Masanori
authors: M
authors: Nojima
authors: Makoto
authors: M
authors: Otsu
authors: Hiromitsu
authors: H
authors: Nakauchi
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000503:physiopathology*; D001855:Bone Marrow Diseases / Q000628:therapy; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction
chemical_list: C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Chemokine receptors; Gene therapy (gene transfer to hematopoietic stem cells); Hematopoietic stem cells (stem and primitive progenitor cells); Stem cell transplantation