Engineering therapies to rejuvenate muscle stem cells from aged tissues
Benjamin D. Cosgrove, Ph.D.1,2, Penney M. Gilbert, Ph.D.1,3, Ermelinda Porpiglia, Ph.D.1, and
Helen M. Blau, Ph.D.1
1Baxter
Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, and Institute for Stem Cell
Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA
2Department of Biomedical Engineering, Cornell University, Ithaca, NY
3Institute of Biomaterials and Biomedical Engineering and Donnelly Centre for Cellular and Biomolecular Research,
University of Toronto, Toronto, Ontario, Canada
Muscle stem cells (MuSCs), also known as satellite cells, are essential to skeletal muscle
regeneration throughout life. In aged individuals, skeletal muscle mass and regenerative
capacity after injury progressively decline, leading to diminished quality of life. We recently
demonstrated that MuSCs prospectively isolated from aged mice have a two-thirds reduction in
regenerative capacity relative to young adult MuSCs, revealing a previously undetected intrinsic
stem cell defect in aged MuSCs. This defect is characterized by premature senescence,
inefficient self-renewal, and is driven by aberrant, cell-autonomous activation of the p38
mitogen-activated protein kinase (MAPK) pathway and underscores the challenge of using
autologous MuSCs as a cell therapeutic for the aged. We show that a population of aged
MuSCs with potent regenerative function can be generated upon transient pharmacological
inhibition of p38 MAPK in conjunction with culture on PEG hydrogel substrate with a rigidity
modulus matching that of healthy skeletal muscle. This combined treatment results in expansion
of a MuSC population with rejuvenated capacity to engraft and serially transplant, and to restore
strength upon delivery to damaged muscles of aged mice. Our more recent results suggest that
the decline of self-renewal function in the aged MuSC population arises from a functionally
defective stem-cell sub-population, defined by a molecular heterogeneous phenotype which
results in an altered mechanosensitivity. Our findings reveal a synergy between biophysical and
biochemical cues that provides a paradigm for an autologous stem cell therapy for localized
muscle injury that could benefit aged individuals.