Muscle stem cells (MuSCs) are responsible for the maintenance and regeneration of skeletal muscle mass, crucial to mobility and quality of life. With advanced age the proportion of MuSCs that is functional in regeneration progressively declines due to cell-intrinsic changes (Cosgrove, Blau, Nature Medicine, 2008). Deficits include aberrantly active cell signaling pathways, increased expression of senescence markers, and a reduction in stem cell proliferative capacity. Establishing the tipping point for this array of cell-intrinsic defects affords a unique opportunity. Our quest is to identify novel therapeutic agents that target and expand the residual robustly regenerative MuSCs in aged muscle tissues, enabling tissue rejuvenation critical to muscle repair in the elderly.

An understanding of MuSCs at the single cell level is key to identifying those with enhanced regenerative properties. To gain insights into young and aged MuSCs we employ cutting edge single cell technologies. We monitor the self-renewal and expansion capacity of single MusCs by non-invasive bioluminescence imaging over time (Sacco, Blau, Nature, 2008). Using hydrogels with an elasticity comparable to muscle tissue (Gilbert, Blau, Science, 2010), we can maintain MuSCs in a stem cell state. We generate time-lapse movies of genealogic lineage trees that track the response of single cells and their progeny to biochemical and biophysical cues within deconstructed niches. Using the Baxter Algorithms developed in our laboratory, we can distinguish symmetric and asymmetric self-renewal behavior, monitor apoptosis, determine division kinetics, cell motility and migration trajectories (Gilbert, Blau, Science, 2010). These algorithms have won first place in International Cell Tracking competitions in 2013, 2014 and 2015 (Maska, Ortiz-de-Solorzano, Bioinformatics, 2014).

Therapeutic applications:

• We are seeking drugs that expand and rejuvenate the function of the aged MuSC population with a view rejuvenating muscles.

• We are using similar analyses to determine the impact of metabolic homeostasis on the muscle wasting that accompanies Type 2 diabetes.

• We are charting the progression of subsets of MuSCs that are sequentially targeted in the course of the most common and disabling genetic muscle wasting disorder, Duchenne Muscular Dystrophy.

A muscle stem cell resident in its muscle fiber niche and stained pink for expression of Pax7, its hallmark transcription factor.

A scanning electron micrograph of a muscle stem cell.

A cross-section of healthy fast and slow contracting skeletal muscle fibers.