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.

Pharmacology of Heparin and Related Drugs

“…In bone tissue engineering, a heparinized scaffold may be used to carry BMP-2 (Noh et al, 2015) and to improve mineralization of mesenchymal stem cells (MSCs) (Honda et al, 2013). Heparin crosslinked to a chitosan scaffold retains FGF-2 and thus sustains survival and growth of neural stem cells for treatment of central nervous system injury (Skop et al, 2013); heparin-gelatin scaffolds have been developed for eye surgery as replacements for cadaveric corneas (Niu et al, 2014).…”

Optimization of drug combinations using Feedback System Control

“…The FSC technique has proven to be helpful in the optimization of the conditions for the maintenance 15 or differentiation 10,12 of stem cells. Another successful application of the FSC method was in the optimization of a flavonoid-based herbal drug combination 19 .…”

Overcoming physical constraints in bone engineering: ‘the importance of being vascularized’

“…A number of growth factors critically contribute to these processes, including VEGF, PDGF, angiopoietins, BMPs, and IGFs. The addition of soluble factors has been recently explored in 2D monocultures of MSCs with innovative approaches (Honda et al, 2013). Beside the paracrine diffusible factors, also physical cell-cell contacts such as connexins are involved (Herzog et al, 2014).…”