The research community is devoting an increasing amount of attention to the use of cellular reprogramming in vivo as a basis for therapies, rather than as a way to produce pluripotent cells outside the body. It has been only fifteen years or so since the first practical reprogramming approach was developed, using Yamanaka factors to transform somatic cells into induced pluripotent stem cells. Only in the past few years have researchers tried in earnest to introduce reprogramming factors into living animals in order to produce benefits to health and tissue function. It is somewhat surprising, perhaps, that this can be done without the immediate consequences of cancer and loss of tissue function, but the dose makes the poison.
Reprogramming of cells not only changes their state, but also resets epigenetic marks characteristic of cells in aged tissues and restores lost mitochondrial function. Research suggests that this beneficial restoration of function can be to some degree decoupled from the change in cell state, and that the process of undergoing programming is a complicated time course, with important differences by cell type, that can be manipulated in numerous ways. Cells can be partially reprogrammed for a short time, gaining restored function, without losing their state and behavior. This is a necessary goal if reprogramming is to be deployed as a therapy to restore function in aging tissues.
Reprogramming of somatic cells to a pluripotent state by overexpressing the Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc [OSKM]) is a long and complex process. Cellular reprogramming is widely utilized for disease modeling in vitro. However, reprogramming in vivo induces tumor development. Our lab showed that partial reprogramming by short-term expression of reprogramming factors ameliorated aging hallmarks without tumor formation, opening a possible application of this approach in vivo. Recently, other reports have demonstrated rejuvenation of dentate gyrus cells, retinal ganglion cells, chondrocytes, and muscle stem cells using reprogramming factors, reinforcing its potential application in clinical settings. Besides amelioration of cellular aging hallmarks, reprogramming factors promote tissue regeneration in aged mice. However, it is unknown whether OSKM-improved regeneration is solely a result of its rejuvenating effect.
Muscle regeneration is primarily mediated by muscle stem cells, also known as satellite cells (SCs), which reside in a characteristic niche located between the basal lamina and plasma membrane of myofibers. The regenerative capacity of SCs is influenced by both intrinsic modulators and the extrinsic microenvironment. We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice, but these studies were performed by expressing OSKM systemically (i.e., in all cell types). It is therefore unclear whether intrinsic or niche-specific factors contributed to the observed improvement in muscle regeneration.
In this work, we generate myofiber- and SC-specific OSKM induction mouse models to investigate the effect of OSKM induction on extrinsic and intrinsic modulators of SCs, respectively. In addition, we chose young mice to investigate whether the improvement of regeneration can be achieved by OSKM induction regardless of its rejuvenating effect. Our data shows that myofiber-specific OSKM induction accelerates muscle regeneration through downregulating the myofiber-secreted niche factor, Wnt4, to induce the activation and proliferation of SCs. In contrast, SC-specific OSKM induction does not improve muscle regeneration in young mice. We conclude that partial reprogramming via OSKM can remodel the SC niche to induce SC activation and proliferation and accelerate muscle regeneration.