Brief Report: Human Pluripotent Stem Cell Models of Fanconi Anemia Deficiency Reveal an Important Role for Fanconi Anemia Proteins in Cellular Reprogramming and Survival of Hematopoietic Progenitors

Fanconi anemia (FA) is a genomic instability disorder caused by mutations in genes involved in replication‐dependant‐repair and removal of DNA cross‐links. Mouse models with targeted deletions of FA genes have been developed; however, none of these exhibit the human bone marrow aplasia. Human embryo...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2013-05, Vol.31 (5), p.1022-1029
Main Authors: Yung, Sun K., Tilgner, Katarzyna, Ledran, Maria H., Habibollah, Saba, Neganova, Irina, Singhapol, Chatchawan, Saretzki, Gabriele, Stojkovic, Miodrag, Armstrong, Lyle, Przyborski, Stefan, Lako, Majlinda
Format: Article
Language:English
Subjects:
Bone marrow
Cell Differentiation - physiology
Cellular Reprogramming - physiology
Embryonic hematopoiesis
Fanconi anemia
Fanconi Anemia - genetics
Fanconi Anemia - metabolism
Fanconi Anemia - pathology
Fanconi Anemia Complementation Group Proteins - genetics
Fanconi Anemia Complementation Group Proteins - metabolism
Genetic Therapy
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Hematopoietic Stem Cells - pathology
Human embryonic stem cells
Humans
Human‐induced pluripotent stem cells
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Induced Pluripotent Stem Cells - pathology
Medical research
Stem cells
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Summary:Fanconi anemia (FA) is a genomic instability disorder caused by mutations in genes involved in replication‐dependant‐repair and removal of DNA cross‐links. Mouse models with targeted deletions of FA genes have been developed; however, none of these exhibit the human bone marrow aplasia. Human embryonic stem cell (hESC) differentiation recapitulates many steps of embryonic hematopoietic development and is a useful model system to investigate the early events of hematopoietic progenitor specification. It is now possible to derive patient‐specific human‐induced pluripotent stem cells (hiPSC); however, this approach has been rather difficult to achieve in FA cells due to a requirement for activation of FA pathway during reprogramming process which can be bypassed either by genetic complementation or reprogramming under hypoxic conditions. In this study, we report that FA‐C patient‐specific hiPSC lines can be derived under normoxic conditions, albeit at much reduced efficiency. These disease‐specific hiPSC lines and hESC with stable knockdown of FANCC display all the in vitro hallmarks of pluripotency. Nevertheless, the disease‐specific hiPSCs show a much higher frequency of chromosomal abnormalities compared to parent fibroblasts and are unable to generate teratoma composed of all three germ layers in vivo, likely due to increased genomic instability. Both FANCC‐deficient hESC and hiPSC lines are capable of undergoing hematopoietic differentiation, but the hematopoietic progenitors display an increased apoptosis in culture and reduced clonogenic potential. Together these data highlight the critical requirement for FA proteins in survival of hematopoietic progenitors, cellular reprogramming, and maintenance of genomic stability. STEM CELLS 2013;31:1022–1029
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1308