title: Guiding the osteogenic fate of mouse and human mesenchymal stem cells through feedback system control.
abstract: Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering.
authors.affiliation: 1] The Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, UCLA School of Dentistry, Box 951668, Los Angeles, CA, 90095, USA [2] Craniofacial Function Engineering and Research Unit for Interface Oral Health Science, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan [3] Institute of Dental Research, Osaka Dental University, 8-1 Kuzuha Hanazonocho, Hirakata-Shi, Osaka, 573-1121, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Honda
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.forename: Federico
authors.initials: F
authors.lastname: Mussano
authors.forename: Akira
authors.initials: A
authors.lastname: Wiberg
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D003470:Culture Media; D051785:Smad Proteins