Stem cell-based regeneration of diseased organs and tissues is the most promising therapeutic avenue to cure human diseases for which there is currently no effective treatment. The therapeutic success of stem cell-based therapies depends on their ability to acquire a specific fate and selectively repopulate target tissues and organs. Devising pharmacological strategies that encourage stem cells to adopt a specialized phenotype is therefore a key issue in regenerative medicine.
From a biological point of view, stem cell commitment to distinct lineages is dictated by the selection of specific sub-sets of genes from the DNA sequence, which is identical in all cells of the same organism. During organogenesis and regeneration, selection of specific genes in pluripotent stem cells is made possible by specific changes of the chromatin – the substance that surrounds the DNA and regulates the accessibility to those proteins that stimulate or repress gene expression. These chromatin changes (often referred as to the “epigenome”) are typically imparted by developmental and regeneration cues, and provide a reasonable target for novel, specific interventions to manipulate stem cells in regenerative medicine.
The lack of knowledge on the mechanisms by which extra-cellular cues are converted into chromatin modifications in stem cells currently precludes the effective application of pharmacological strategies to manipulate stem cells in regenerative medicine.
This proposal will fill this gap by elucidating the basic principles that regulate the ability of stem cells to become muscle progenitors, and by identifying the mechanism by which external cues are converted into epigenetic changes that regulate proliferation and differentiation of hESC-derived muscle cells.
The overall goal of this research is to identify chromatin targets of pharmacological tools that can selectively manipulate stem cells toward the desired fate. Specifically, this proposal will provide the molecular rationale for the generation of muscle progenitors from hESCs and for their pharmacological manipulation in order to regenerate diseased muscles.
We anticipate that this proposal will have a strong impact in the regenerative medicine for neuromuscular diseases, as it will provide the molecular insight to devise optimal strategies for stem-cell mediated regeneration in the treatment of muscular disorders with different pathogenesis. We envision diseases-specific therapeutic strategies based either on pharmacological control of endogenous adult muscle stem cells, when available (as in the case of early stages of muscular dystrophies), or hESC-mediated repopulation of dieased muscles, which have a deficient or exhausted potential for endogenous regeneration (i.e. late stages of muscular dystrophies or atrophic muscles).
The increased life span in the population of developing countries and states, such as California, poses a number of new issues related to the health control and social assistance in elderly population. For instance, the age-associated muscle atrophy (sarcopenia), and the muscle catabolism occurring as a consequence of chronic diseases (i.e. cancer cachexia, AIDS or chronic infections, terminal stages of cardiovascular diseases) or prolonged pharmacological treatments (i.e. chemotherapy) lead to a reduced performance, increased morbidity, and request for medical and social assistance for an increasing percentage of the Californian population.
Thus, the identification of pharmacological strategies toward regenerating aged or diseased skeletal muscles is a critical task for the development of future health strategies in California.
Furthermore, the identification of stem cell-mediated strategies in regenerative medicine will fuel hopes for the treatment of genetic neuromuscular diseases, such as muscular dystrophies, and will reduce the emotional, social and economic impact that patients confined to wheel chair have on public opinion and health.
More in general, the discovery of pharmacological applications for stem cell employment in neuromuscular diseases will help to establish a leadership in regenerative medicine, will inspire new technologies and will give the impetus to new initiatives attracting financial resources and a new generation of stem cell scientists in California.
The generation of stem cell scientists is particularly important to create and propagate in the future a productive environment fueling the research in regenerative medicine. This proposal will also be instrumental to train and commit to the stem cell research new MD and PhD scientists that will provide a valuable resource to propel the advances in regenerative medicine in California.