2013 - CTS 2013 Congress

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State of the Art: Cardiovascular System, Skin, and Other Tissues

4.1 - Exhaustion of Muscle Progenitor Cells during Aging & Disease: Implication for Stem Cell Therapy

Presenter: Johnny, Huard, Pittsburgh, United States
Authors: Johnny Huard

Aging is characterized by the progressive erosion of tissue homeostasis and functional reserve in all organ systems. Although controversy remains as to the molecular mechanism(s) underlying the process of aging, accumulated cellular damage, including DNA damage, appears to be a major determinant of lifespan as well as age-related pathologies. Moreover, there is evidence that the accumulation of damage in stem cells renders them defective for self-renewing and regenerating damaged tissues. We have recently demonstrated that a population of muscle progenitor cells(MPCs) isolated from the ERCC1-deficient mouse model of accelerated aging, are defective in their proliferation abilities, differentiation capacity and resistance to oxidative stress.  We have observed that intraperitoneal (IP) injections of wild-type (WT)-MPCs into Ercc1 knockout (Ercc1-/-) mice resulted in an improvement in age related pathologies. Although the mechanisms by which the transplantation of WT-MPCs extend the lifespan of these progeria mice is still under investigation, we have obtained evidence that the beneficial effect imparted by the injected cells occur through a paracrine effect that involve angiogenesis.

Duchenne muscular dystrophy (DMD) is a fatal genetic disease characterized by a deficiency in dystrophin and the progressive wasting of the patient’s muscles. Current treatments for DMD have centered on the restoration of dystrophin; however, they were fraught with serious limitations. Interestingly, DMD patients lack dystrophin from the time of birth; however, the onset of muscle weakness only becomes apparent at 4-7 years of age, which happens to coincide with the exhaustion of the muscle progenitor cell (MPC) pool. There are several lines of evidence that support this concept including the gradual impairment of the myogenic potential of MPCs isolated from DMD patients during aging which results in a reduction of muscle regeneration in older DMD patients. In contrast to that observed with MPCs isolated from the mdx mice (dystrophin deficient and mild phenotype), we have recently shown a defect in the MPCs isolated from double Knock-Out (dKO) mouse (dystrophin/utrophin deficient and severely affected). We have recently observed that the MPC defect from the dKO mouse model appears to be age dependent and not specific to MPC since other stem cell population also appears to be affected. These results taken together support the concept that the rapid disease progression associated with the dKO model, is related to a defect in the stem cell pool, as observed in DMD patients. We have also obtained preliminary data indicating that the defect in dKO-MPC appears to be related, at least in part, to the notch and NF-kB signaling pathway, negative regulator of myogenesis and muscle growth. Our recent works indicate that stem cell defect in dKO mice, not only leads to muscle abnormalities and weakness but also to other abnormalities of the musculoskeletal system, including bone morphology and healing capacity. We have investigated potential approaches to rescue the defect in dKO MPCs by blocking the notch pathway as well as the inflammatory mediator and negative regulator of muscle growth, NF-kB in vitro and potentially rescue the overall histopathology of the dKO mice after MPC implantation in vivo. This technology could be very helpful for altering DMD progression through the reduction of stem cell exhaustion and modulation of inflammation.


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