TY - JOUR
T1 - Efficient hematopoietic differentiation of human embryonic stem cells on stromal cells derived from hematopoietic niches
AU - Ledran, Maria H.
AU - Krassowska, Anna
AU - Armstrong, Lyle
AU - Dimmick, Ian
AU - Renström, Jonas
AU - Lang, Roland
AU - Yung, Sun
AU - Santibanez-Coref, Mauro
AU - Dzierzak, Elaine
AU - Stojkovic, Miodrag
AU - Oostendorp, Robert A.J.
AU - Forrester, Lesley
AU - Lako, Majlinda
N1 - Funding Information:
The authors are grateful to Bronia Baker and Dr. Xiao Nong Wang for help with staining of cytospin slides; Professor Paul Flecknell, Dr. Patrick Hays, and Robert Stewart for help with the animal work; and Dennis Kirk for technical assistance. We would like to extend out thanks to Professor Susan Lindsay for providing cDNA from human embryos and to Complement Genomics Plc. for carrying out the fingerprinting analysis. We are also very grateful to Jackson Lab for providing the recipient mice and advice on their maintenance. This study was supported by Leukemia Research Fund, UK (LRF), grant number 04043, One North East Regional Development Agency, and Life Knowledge Park.
PY - 2008/7/3
Y1 - 2008/7/3
N2 - Hematopoietic stem cells derived from human embryonic stem cells (hESCs) could provide a therapeutic alternative to bone marrow transplants, but the efficiency of currently available derivation protocols is low. In this study, we investigated whether coculture with monolayers of cells derived from mouse AGM and fetal liver, or with stromal cell lines derived from these tissues, can enhance hESC hematopoietic differentiation. We found that under such conditions hESC-derived differentiating cells formed early hematopoietic progenitors, with a peak at day 18-21 of differentiation that corresponded to the highest CD34 expression. These hESC-derived hematopoietic cells were capable of primary and secondary hematopoietic engraftment into immunocompromised mice at substantially higher levels than described previously. Transcriptional and functional analysis identified TGF-β1 and TGF-β3 as positive enhancers of hESC hematopoietic differentiation that can further stimulate this process when added to the culture. Overall, our findings represent significant progress toward the goal of deriving functional hematopoietic stem cells from hESCs.
AB - Hematopoietic stem cells derived from human embryonic stem cells (hESCs) could provide a therapeutic alternative to bone marrow transplants, but the efficiency of currently available derivation protocols is low. In this study, we investigated whether coculture with monolayers of cells derived from mouse AGM and fetal liver, or with stromal cell lines derived from these tissues, can enhance hESC hematopoietic differentiation. We found that under such conditions hESC-derived differentiating cells formed early hematopoietic progenitors, with a peak at day 18-21 of differentiation that corresponded to the highest CD34 expression. These hESC-derived hematopoietic cells were capable of primary and secondary hematopoietic engraftment into immunocompromised mice at substantially higher levels than described previously. Transcriptional and functional analysis identified TGF-β1 and TGF-β3 as positive enhancers of hESC hematopoietic differentiation that can further stimulate this process when added to the culture. Overall, our findings represent significant progress toward the goal of deriving functional hematopoietic stem cells from hESCs.
UR - http://www.scopus.com/inward/record.url?scp=48649109860&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2008.06.001
DO - 10.1016/j.stem.2008.06.001
M3 - Article
C2 - 18593561
AN - SCOPUS:48649109860
SN - 1934-5909
VL - 3
SP - 85
EP - 98
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -