Department of Bioengineering
University of California, Berkeley
The maintenance and repair of multiple organ systems deteriorate with age, which causes a multitude of debilitating degenerative disorders in the elderly, eroding their quality of life and costing billions of dollars in health care; clearly there is a need for a better understanding of why the stem cells dedicated to organ maintenance and repair fail with advancing age.
One key direction of my laboratory is to understand how canonical signal transduction networks (such as Notch, TGF-beta/BMP, Wnt/b-catenin, MAPK), regulate the behavior of organ stem cells in young versus aged tissues: muscle, brain, skin, etc., with the goal to identify common age-imposed alterations that are responsible for pathological degenerative changes. The translational ramification of this research is in engineering effective and tightly controlled tissue regenerative responses by “youthful” modification of such key regulatory age-specific signals. The initial work has been promising in simultaneous enhancement of myogenesis and hippocampal neurogenesis in the same old mouse by one systemically administered small molecule, Alk5 inhibitor of TGF-beta pathway (Oncotarget, 2015), as well as by enhancing myogenesis and combatting obesity in the same old mouse by systemically administered oxytocin (Nature Communications, 2014).
Heterochronic parabiosis studies provided a proof of principle that tissue stem cells residing in an old mammal are capable of productive regenerative responses; their boost can enhance maintenance and repair of multiple organs, preventing or ameliorating debilitating degeneration of muscle, bone, liver, brain, etc. that invariably accompany human aging (Nature 2005, Cell Cycle, 2012). In agreement with the notion that tissue stem cells do not succumb to significant intrinsic aging, we have established that effective telomerase activity and no accumulation of DNA damage are displayed by the aged satellite cells (Plos One, 2013). The current approaches of Conboy laboratory: are (1) to simplify the parabiotic procedure and make it better controlled by development of heterochronic plasmapheresis; and (2) to explore the connection between the aging of circulatory milieu and cellular senescence.
To uncover a more feasible than “young blood” yet physiological way of restoring youthful regeneration to old tissues, are studying the secretome of human embryonic stem cells, which are capable of robust organogenesis, and thus we reasoned create optimal stem and progenitor cell environments. We have found that proteins produced by human embryonic stem cells (hESCs) promote and rejuvenate the myogenic capacity of muscle stem/progenitor cells, enhance the proliferation of neuronal progenitor cells and promote the viability of human cortical neurons in a model of Alzheimer’s disease (Aging 2011, 2013). As we progress to the molecular identification of these therapeutic compounds, we have established that they contain heparin-binding domains and can be enriched with heparin-coated beads (Aging 2013, UC provisional patent). Our current work published in Aging 2014 extends these findings to human progenitors and uncovers the molecular mechanism of action: hESC-secreted proteins act in conserved fashion in human and mouse by activating the MAPK and Notch pathways, where Delta/Notch-1 activation is dependent on pERK. We plan to substantiate these studies by a proteomics investigation, look for cross-tissue conservation between muscle and brain, identify most or all of the soluble proteins that are secreted by hESCs and that enhance the regeneration and maintenance of postnatal tissues, and comprehensively determine the gene expression and epigenetic changes that are caused by the exposure of adult and old cells to these pro-regenerative factors.
Other directions of our laboratory are: Stem cell asymmetries (J. Cell Biology, 2013), Analysis of stem cell heterogeneity at single levels (Integrative Biology, 2013), Studies of myogenesis in diabetes (Acta Pharmacol. Sin. 2013), Age-related inflammatory increase and its effects on muscle repair (Aging, 2012), Generation of novel myogenic cells by de-differentiation of muscle fibers (Chemistry and Biology, 2011, US Patent Issued), Epigenetic effects of MAPK/pERK (Stem Cells, 2015).
Success in this research program will improve our understanding of the regulation of stem cell behavior, will uncover the molecular causes for abandonment of tissue maintenance and repair by the dedicated stem cells in old mammals and will enable rational approaches for delaying the devastating regenerative decline that invariably accompanies human aging and manifests in severe pathologies, afflicting person’s strength, agility and cognition.