Muscle stem cells (MuSCs), also known as satellite cells, are essential to muscle regeneration throughout life [1]. In aging, skeletal muscle mass and regenerative capacity after injury progressively decline, leading to diminished quality of life in aged individuals [2]. Efforts to explain the dysfunction of aged skeletal muscle tissue have focused on aging-related changes in tissue microenvironment factors restricting MuSC function [3]. In my postdoctoral research, I have demonstrated, using non-invasive imaging assays of tissue regeneration, that MuSCs prospectively isolated from old mice have a marked reduction in regenerative capacity relative to young MuSCs, revealing a previously undetected intrinsic stem cell defect in old MuSCs. Further, I have identified a novel ex vivo strategy to overcome the regenerative dysfunction of old MuSCs;treatment of old MuSCs maintained on a soft biomimetic hydrogel platform [4] with a small molecule inhibitor of p38 mitogen- associated protein kinase yields an expansion in absolute numbers of functional stem cells and restores their function in regeneration to that of young MuSCs. This approach offers promise for rejuvenating and increasing the numbers of MuSCs and could enable localized autologous stem cell therapy for muscle wasting in aged individuals, for which there are no pharmacologic treatments in clinical use. I propose to merge prior training in bioengineering and stem cell biology with new training in muscle physiology and systems biology to further investigate the regenerative dysfunction of MuSCs in aging and its rescue ex vivo.
In Aim 1 (K99 phase), I will evaluate whether ex vivo-treated old MuSCs can rescue defective muscle regeneration and increase muscle strength in old mice and are capable of long-term rejuvenated function in response to successive regenerative demands.
In Aim 2 (bridging K99/R00 phases), I will elucidate whether defective regenerative function is a homogeneous or heterogeneous phenotype in old MuSCs by combining multi-parameter mass cytometry (CyTOF) [5] and SPADE algorithm [6] analysis with sensitive transplantation assays to identify and compare the regenerative functions of MuSC sub-populations isolated from young and old mice.
In Aim 3 (R00 phase), I will elucidate dysregulated signaling network mechanisms underlying the stem cell dysfunction of old MuSCs for improved therapeutic treatment using signaling network- level systems biology approaches [7]. This Transition to Independence proposal describes research and career development activities, including conference attendance and course training that will establish me as a competitive candidate for an independent faculty position and aid my development of an innovative, successful research program in the biology and treatment of stem cell aging. These activities will be mentored by Drs. Helen Blau (primary), Scott Delp (co-mentor), and Garry Nolan (co-mentor) at Stanford University, which is a world-class stem cell biology research institution.

Public Health Relevance

Skeletal muscle is maintained and regenerated through the action of adult stem cells that reside in muscle tissue throughout the lifespan of an individual. I aging, muscle atrophies and does not regenerate from injury efficiently, diminishing quality of life, due to a reduced regenerative capacity of muscle stem cells. This proposal focuses on gaining insights and developing strategies towards providing therapy to defective muscle stem cells from aged individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
5K99AG042491-02
Application #
8515285
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Williams, John
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$88,332
Indirect Cost
$6,543
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Cosgrove, Benjamin D; Gilbert, Penney M; Porpiglia, Ermelinda et al. (2014) Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20:255-64