A Darwinian and Physical Look at Stem Cell Biology Helps Understanding the Role of Stochasticity in Development. Front

International audienceSingle-cell analysis allows biologists to gain huge insight into cell differentiation and tissue structuration. Randomness of differentiation, both in vitro and in vivo, of pluripotent (multipotent) stem cells is now demonstrated to be mainly based on stochastic gene expression. Nevertheless, it remains necessary to incorporate this inherent stochasticity of developmental processes within a coherent scheme. We argue here that the theory called ontophylogenesis is more relevant and better fits with experimental data than alternative theories which have been suggested based on the notions of self-organization and attractor states. The ontophylogenesis theory considers the generation of a differentiated state as a constrained random process: randomness is provided by the stochastic dynamics of biochemical reactions while the environmental constraints, including cell inner structures and cell-cell interactions, drive the system toward a stabilized state of equilibrium. In this conception, biological organization during development can be seen as the result of multiscale constraints produced by the dynamical organization of the biological system which retroacts on the stochastic dynamics at lower scales. This scheme makes it possible to really understand how the generation of reproducible structures at higher organization levels can be fully compatible with probabilistic behavior at the lower levels. It is compatible with the second law of thermodynamics but allows the overtaking of the limitations exhibited by models only based on entropy exchanges which cannot cope with the description nor the dynamics of the mesoscopic and macroscopic organization of biological systems