Molecular and Epigenetic Regulation of Stem Cell Self-Renewal and Differentiation
Mesenchymal stem cells (MSCs) are capable of differentiating into osteoblasts and adipocytes, and the dysregulation of MSC lineage specification may lead to the imbalance between bone mass and fat tissue, which finally result in osteoporosis. Our previous study has shown the critical role of KDM4B in promoting osteogenic differentiation and reducing adipogenic differentiation of MSCs in vitro, but the in vivo function of KDM4B remains to be investigated. In this study, Global deletion of Kdm4b and deletion of Kdm4b in mesenchymal progenitors, but not in mature osteoblasts, enhanced age-related bone loss and adipose accumulation in mouse bone marrow. Deletion of Kdm4b in mesenchymal progenitors also promoted bone loss and adipose accumulation induced by estrogen deficiency respectively. Restoration of KDM4B successfully reinstated ALP activity, mineralization and expression of osteogenic-related genes, and inhibited adipogenesis of BMSCs from Prx1-Cre;Kdm4bfl/fl mice. Furthermore, Kdm4b was required for the self-renewal of mouse MSCs, as determined by colony formation assay and serial transplantation assay. Collectively, Kdm4b was required for bone homeostasis by promoting osteogenic differentiation and reducing adipogenic differentiation of MSCs in vivo. Kdm4b was also required for self-renewal of MSCs. Targeting KDM4B may facilitate the prevention and therapy of osteoporosis, and also be used in MSC-based bone regeneration. In addition, we reported an efficient ex vivo culture protocol to derive functional MSCs from human ESCs by inhibition of NFκB. We found inhibition of NFκB promoted loss of the pluripotent markers during differentiation of human ESCs, and increased expression of mesenchymal lineage markers. Microarray analysis revealed that the genes regulated by inhibition of NFκB signaling are associated with developmental process and cell differentiation during human ESC differentiation. Finally, the purified MSCs showed multipotency in vitro. Our data provides key insights into the role of NFκB in mesenchymal lineage specification of human ESCs and provide a novel method for generation of MSCs.