An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia
Yuan Zhou,
Yongzheng He,
Wen Xing,
Peng Zhang,
Hui Shi,
Shi Chen,
Jun Shi,
Jie Bai,
Steven D. Rhodes,
Fengqui Zhang,
Jin Yuan,
Xianlin Yang,
Xiaofan Zhu,
Yan Li,
Helmut Hanenberg,
Mingjiang Xu,
Kent A. Robertson,
Weiping Yuan,
Grzegorz Nalepa,
Tao Cheng,
D. Wade Clapp,
Feng-Chun Yang
Affiliations
Yuan Zhou
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China;Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Yongzheng He
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Wen Xing
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China;Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Peng Zhang
Sylvester Comprehensive Cancer Center, Miami, FL, USA;Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Hui Shi
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China;Sylvester Comprehensive Cancer Center, Miami, FL, USA;Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Shi Chen
Sylvester Comprehensive Cancer Center, Miami, FL, USA;Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Jun Shi
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Jie Bai
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Steven D. Rhodes
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Fengqui Zhang
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Jin Yuan
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Xianlin Yang
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Xiaofan Zhu
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Yan Li
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Helmut Hanenberg
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, Düsseldorf, Germany
Mingjiang Xu
Sylvester Comprehensive Cancer Center, Miami, FL, USA;Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Kent A. Robertson
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Weiping Yuan
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
Grzegorz Nalepa
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Tao Cheng
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
D. Wade Clapp
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA;Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
Feng-Chun Yang
Sylvester Comprehensive Cancer Center, Miami, FL, USA;Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.
