TY - JOUR
T1 - Induction of a hemogenic program in mouse fibroblasts
AU - Pereira, Carlos Filipe
AU - Chang, Betty
AU - Qiu, Jiajing
AU - Niu, Xiaohong
AU - Papatsenko, Dmitri
AU - Hendry, Caroline E.
AU - Clark, Neil R.
AU - Nomura-Kitabayashi, Aya
AU - Kovacic, Jason C.
AU - Ma'Ayan, Avi
AU - Schaniel, Christoph
AU - Lemischka, Ihor R.
AU - Moore, Kateri
N1 - Funding Information:
We thank D. Tenen (Harvard Medical School) for the huCD34tTa transgenic mouse. We thank D.F. Lee, Y.S. Ang, S. Mulero-Navarro, A. Freire, and the members of the Lemischka/Moore laboratory for useful discussions and Y. Liu for laboratory management. We would like to thank M. Rendl and V. Gouon-Evans and their laboratories for their assistance. We thank T. Schroeder and K. Kokkaliaris for advice with live imaging and F. González for inducible vectors. We thank M. Baron and S. Ghaffari for critical reading of the manuscript. We would also like to thank the Mount Sinai hESC/hiPSC Shared Resource Facility and S. D’Souza for help with materials and protocols and the Mount Sinai Genomics, Flow Cytometry, and Mouse facilities. C.F.P. is a recipient of an EMBO Long-term Postdoctoral Fellowship. J.C.K. and A.N.K are supported by the NIH grants 5K08HL111330 and 5T32HL007824-15; A.M. by R01GM098316 and R01DK088541.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition. We attempted to induce this process in mouse fibroblasts by screening a panel of factors for hemogenic activity. We identified a combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6, that efficiently induces endothelial-like precursor cells, with the subsequent appearance of hematopoietic cells. The precursor cells express a human CD34 reporter, Sca1, and Prominin1 within a global endothelial transcription program. Emergent hematopoietic cells possess nascent hematopoietic stem cell gene-expression profiles and cell-surface phenotypes. After transgene silencing and reaggregation culture, the specified cells generate hematopoietic colonies in vitro. Thus, we show that a simple combination of transcription factors is sufficient to induce a complex, dynamic, and multistep developmental program in vitro. These findings provide insights into the specification of definitive hemogenesis and a platform for future development of patient-specific stem and progenitor cells, as well as more-differentiated blood products.
AB - Definitive hematopoiesis emerges during embryogenesis via an endothelial-to-hematopoietic transition. We attempted to induce this process in mouse fibroblasts by screening a panel of factors for hemogenic activity. We identified a combination of four transcription factors, Gata2, Gfi1b, cFos, and Etv6, that efficiently induces endothelial-like precursor cells, with the subsequent appearance of hematopoietic cells. The precursor cells express a human CD34 reporter, Sca1, and Prominin1 within a global endothelial transcription program. Emergent hematopoietic cells possess nascent hematopoietic stem cell gene-expression profiles and cell-surface phenotypes. After transgene silencing and reaggregation culture, the specified cells generate hematopoietic colonies in vitro. Thus, we show that a simple combination of transcription factors is sufficient to induce a complex, dynamic, and multistep developmental program in vitro. These findings provide insights into the specification of definitive hemogenesis and a platform for future development of patient-specific stem and progenitor cells, as well as more-differentiated blood products.
UR - http://www.scopus.com/inward/record.url?scp=84881149632&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2013.05.024
DO - 10.1016/j.stem.2013.05.024
M3 - Article
AN - SCOPUS:84881149632
SN - 1934-5909
VL - 13
SP - 205
EP - 218
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 2
ER -