title: Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.
abstract: Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis.
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
authors.forename: Laurence C
authors.initials: LC
authors.lastname: Cheung
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Strickland
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
authors.forename: Meegan
authors.initials: M
authors.lastname: Howlett
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.
authors.forename: Jette
authors.initials: J
authors.lastname: Ford
authors.affiliation: Princess Margaret Hospital, Perth, WA, Australia School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia.
authors.forename: Adrian K
authors.initials: AK
authors.lastname: Charles
authors.affiliation: University of California, Los Angeles, CA, USA.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Lyons
authors.affiliation: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Brigstock
authors.affiliation: Department of Pathology, University Medical Center Utrecht, the Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Princess Margaret Hospital, Perth, WA, Australia School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, Australia.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Cole
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, The University of Melbourne, VIC, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia ursula.kees@telethonkids.org.au.
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Kees
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000637:transplantation; D015851:Interleukin-7 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D038041:Lymphopoiesis / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D015851:Interleukin-7; D050799:STAT5 Transcription Factor; D055513:Connective Tissue Growth Factor
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