Small molecule-driven direct conversion of human pluripotent stem cells into functional osteoblasts.
The abilities of human pluripotent stem cells (hPSCs) to proliferate without phenotypic alteration and to differentiate into tissue-specific progeny make them a promising cell source for regenerative medicine and development of physiologically relevant in vitro platforms. Despite this potential, efficient conversion of hPSCs into tissue-specific cells still remains a challenge. Herein, we report direct conversion of hPSCs into functional osteoblasts through the use of adenosine, a naturally occurring nucleoside in the human body. The hPSCs treated with adenosine not only expressed the molecular signatures of osteoblasts but also produced calcified bone matrix. Our findings show that the adenosine-mediated osteogenesis of hPSCs involved the adenosine A2bR. When implanted in vivo, using macroporous synthetic matrices, the human induced pluripotent stem cell (hiPSC)-derived donor cells participated in the repair of critical-sized bone defects through the formation of neobone tissue without teratoma formation. The newly formed bone tissues exhibited various attributes of the native tissue, including vascularization and bone resorption. To our knowledge, this is the first demonstration of adenosine-induced differentiation of hPSCs into functional osteoblasts and their subsequent use to regenerate bone tissues in vivo. This approach that uses a physiologically relevant single small molecule to generate hPSC-derived progenitor cells is highly appealing because of its simplicity, cost-effectiveness, scalability, and impact in cell manufacturing, all of which are decisive factors for successful translational applications of hPSCs.
Materials Science and Engineering Program, University of California, San Diego, La Jolla, CA 92093, USA.
Heemin
H
Kang
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Yu-Ru V
YR
Shih
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Manando
M
Nakasaki
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Harsha
H
Kabra
Materials Science and Engineering Program, University of California, San Diego, La Jolla, CA 92093, USA.; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Shyni
S
Varghese
D000241:Adenosine / Q000008:administration & dosage*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D009928:Organ Specificity; D010006:Osteoblasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D044968:Regenerative Medicine
D000241:Adenosine
Pluripotent stem cells; adenosine receptors; adenosine signaling; bone repair; osteogenic differentiation; small molecule