An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.
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 bothFanccandFancggenes 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.
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.
Yuan
Y
Zhou
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Yongzheng
Y
He
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.
Wen
W
Xing
Sylvester Comprehensive Cancer Center, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Peng
P
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.|Sylvester Comprehensive Cancer Center, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Hui
H
Shi
Sylvester Comprehensive Cancer Center, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Shi
S
Chen
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Jun
J
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
J
Bai
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Steven D
SD
Rhodes
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Fengqui
F
Zhang
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Jin
J
Yuan
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Xianlin
X
Yang
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Xiaofan
X
Zhu
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Yan
Y
Li
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.
Helmut
H
Hanenberg
Sylvester Comprehensive Cancer Center, Miami, FL, USA.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Mingjiang
M
Xu
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Kent A
KA
Robertson
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Weiping
W
Yuan
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
Grzegorz
G
Nalepa
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
Tao
T
Cheng
Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA fxy37@med.miami.edu dclapp@iupui.edu.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
D Wade
DW
Clapp
Sylvester Comprehensive Cancer Center, Miami, FL, USA fxy37@med.miami.edu dclapp@iupui.edu.|Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
Feng-Chun
FC
Yang
D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001842:Bone and Bones / Q000002:abnormalities / Q000503:physiopathology; D019070:Cell Lineage; D060833:Cellular Microenvironment; D005199:Fanconi Anemia / Q000473:pathology* / Q000503:physiopathology; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D052218:Fanconi Anemia Complementation Group C Protein