The role of connective tissue growth factor in hematopoiesis

[Truncated abstract] Background: Hematopoiesis is a tightly regulated multi-stage process, predominantly occurring in fetal liver before birth and in the bone marrow postnatally. All hematopoietic cells are derived from a small population of hematopoietic stem cells (HSCs), in which the differentiation and self-renewal properties of HSCs are governed by signals derived from cellular and acellular components that constitute the complex bone marrow microenvironment or niches. Bone marrow stromal cells (BMSCs), osteoblastic cells and endothelial cells critically support the process via direct cell contact, cytokines and growth factors. Connective tissue growth factor (CTGF) is an extracellular matrix-associated protein that is known to regulate skeletogenesis, angiogenesis, osteoclastogenesis as well as osteoblastogenesis in the bone marrow microenvironment, and has been implicated in hematopoietic malignancy, however its role in hematopoiesis has not been determined. Methods: Hematopoietic system in Ctgf+/- and Ctgf-/- mice was examined. Using multi-colour flow cytometric analyses, different lineage populations in various hematopoietic organs from Ctgf-/- and wild type (WT) mice were enumerated. Because Ctgf-/- mice died perinatally, the hematopoietic potential of cells from Ctgf-/- and WT fetal livers was compared using chimera transplantation models. Furthermore, mRNA expression of Ctgf was examined in the bone marrow compartment. In order to gain insight into the function of Ctgf in the bone marrow microenvironment, B-cell maturation was examined in a novel Ctgf-/- BMSC culture system. Lastly, the regulatory role of CTGF in B-cell development was investigated in vitro using recombinant CTGF and IL-7...