Periodic Reporting for period 4 - MacAGE (Macrophage aging and rejuvenation)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
Macrophages are immune cells that are present in essentially every organ of the body. Besides classical functions in immunity, they are also important for normal functioning of the surrounding tissue and its regeneration. Resident macrophages can originate from embryonic progenitors and be maintained in tissues long term by local proliferation. This self-renewal ability, however, appears to decline with age, with potentially major consequences for the response to infection, the resolution of inflammation and the ability for tissue regeneration. Understanding the mechanisms of macrophage aging may thus hold great promise in diseases increasing with old age, including degenerative disease and cancer. We want to decipher the molecular and cellular parameters of macrophage self-renewal and aging. We believe that this understanding will lead to new treatments of such diseases based on manipulating macrophage activity states and macrophage cellular therapies.
We have identified age-associated changes in gene expression and epigenetic identity of tissue macrophage populations and identified transcriptional and epigenetic regulators of age associated changes. We have used several complementary genetic mouse and cell culture models to investigate their role in macrophage activation and self-renewal. This knowledge has led to the development of self-renewing macrophages for cellular therapy. We could show that epigenetic identity of ex vivo expanded macrophages can be maintained through long culture periods and transplantation in vivo (PMID: 35210623). These findings are currently exploited in the ERC proof of concept grant “ONCOMAC”, that aims at the development of self-renewing macrophages for clinical applications against cancer.
Macrophages hold great promise for cell therapy in degenerative disease and cancer. Previously, the development of such therapies has been hampered by the inability of macrophages to proliferate in cell culture. Our discovery that macrophages can be extensively expanded in culture without epigenetic harm is a major discovery that provides a highly positive outlook for the clinical use of macrophage cellular therapies. Further optimizations will be possible through the manipulation of the pathways we identified in aging macrophages. The results obtained with the support of this ERC funding will thus put macrophage cellular therapies on the map of new innovative ‘living drugs’ that will benefit society for the treatment of major age-related diseases, including degenerative disease in many organs and cancer.