Submitted July 24, 2008
Accepted December 14, 2008
Mesenchymal stem/progenitor cells promote the reconstitution of exogenous hematopoietic stem cells in Fancg-/- mice in vivo
Yan Li, Shi Chen, Jin Yuan, Yanzhu Yang, Jingling Li, Jin Ma, Xiaohua Wu, Marcel Freund, Karen Pollok, Helmut Hanenberg, W. Scott Goebel, and Feng-Chun Yang*
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
Department of Pediatric Oncology, Hematology and Clinical Immunology, Children's Hospital, Heinrich Heine University, Duesseldorf, Germany
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States
* Corresponding author; email: fyang{at}iupui.edu.
Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow failure and complex congenital anomalies. While mutations in FA genes result in a characteristic phenotype in the hematopoietic stem/progenitor cells (HSPC), little is known regarding the consequences of a nonfunctional FA pathway in other stem/progenitor cell compartments. Given the intense functional interactions between HSPCs and the mesenchymal microenvironment, we investigated the FA pathway on the cellular functions of murine mesenchymal stem/progenitor cells (MSPC) and their interactions with HSPC in vitro and in vivo. Here, we show that loss of the murine homologue of FANCG (Fancg) results in a defect in MSPC proliferation and in their ability to support the adhesion and engraftment of murine syngeneic HSPCs in vitro or in vivo. Transplantation of wildtype (WT) but not Fancg-/- MSPCs into the tibiae of Fancg-/- recipient mice enhances the HSPC engraftment kinetics, the BM cellularity and the number of progenitors per tibia of WT HSPCs injected into lethally irradiated Fancg-/- recipients. Collectively, these data demonstrate that FA proteins are required in the BM microenvironment to maintain normal hematopoiesis and provide genetic and quantitative evidence that adoptive transfer of WT MSPCs enhances hematopoietic stem cell engraftment.
