Cell division arrest and self-renewal potential of differentiated neurons and heart muscle cells
Description: Onze weefsels en organen verouderen en kunnen beschadigd raken. Het hart en de hersenen zijn de meest kritische lichaamsonderdelen, terwijl juist deze organen slecht in staat zijn om schade te herstellen. De gespecialiseerde spiercellen van het hart en zenuwcellen in de hersenen kunnen zich niet meer vernieuwen door celdeling. Daardoor leidt verlies van deze cellen snel tot verlies van functie, en kunnen aandoeningen als hart- en vaatziekten of dementie ontstaan en moeilijk genezen. Het gehonoreerde onderzoek is gericht op ontdekken waarom gespecialiseerde cellen niet meer delen. De onderzoekers gaan proberen om de remmen op celdeling tijdelijk op te heffen, zodat nieuwe zenuwcellen en hartspiercellen kunnen ontstaan. Studies in een eenvoudig diermodel worden daarbij gebruikt als leidraad voor experimenten met menselijke stamcellen, zenuwcellen en hartspiercellen. De in dit project verworven kennis en begrip kunnen de basis vormen van belangrijke klinische toepassingen in de toekomst.\n\nApplication summary: Therapies that promote tissue regeneration are in great societal demand. While progress has been made in several areas, it appears a long way before degenerating neurons or damaged heart muscle cells can be replaced in patients. Neurodegenerative diseases such as Alzheimer’s disease cause progressive loss of neuronal function and ultimately neuronal death, and are widespread among our aging population. Also common in the Western world are myocardial infarcts (heart attacks), which lead to death of cardiomyocytes, formation of scar tissue and potentially heart failure. While the brain and heart are our most vital organs, both display an inherently low potential for regeneration and repair. Tissue specific stem cells are primarily responsible for the physiological replacement of somatic cells. These stem cells combine self-renewal with the generation of daughter cells that acquire specialized functions (differentiation). Differentiating cells normally exit the division cycle and become permanently arrested. This post-mitotic state prevents uncontrolled expansion, but also limits tissue regeneration. Means to control cell cycle exit of committed precursors or fully differentiated cells would greatly advance regenerative possibilities. While long thought irreversible, recent studies have shown a remarkable plasticity of the differentiated state. Differentiated somatic cells can be reprogrammed to pluripotent stem cells (iPSCs), which has sparked enormous hope for de-differentiation/regeneration therapies. Such strategies still face major hurdles, however, including the need to differentiate iPSCs into the correct specialized cell types in the right numbers. Here, we propose a conceptually simpler regeneration opportunity by seeking to expand the proliferative capacity of lineage-committed precursor cells and inducing cell cycle reentry in post-mitotic cells without erasing lineage commitment. The goal of this project is to obtain a deeper understanding of the mechanisms responsible for cell cycle arrest during differentiation, and to identify ways to gain control over the cell cycle entry-exit decision. We propose to bring together three research groups with complementary expertise in sophisticated differentiation/proliferation models. This will allow taking advantage of the strengths of each system, and revealing general underlying regulatory mechanisms. We will combine studies of i) muscle and neuronal differentiation in the genetically tractable C. elegans model, with ii) well-defined neuronal differentiation in the rodent brain and human induced pluripotent stem cells (iPSCs), and iii) mouse models of heart disease and human patient material. This combined strategy will likely reveal that interfering with cell-cycle arrest at multiple levels (G1 control, transcriptional regulation and miRNAs) can be applied to prevent and revert the transition from proliferation precursor to post-mitotic differentiated cell.
Funder: ZonMw
Funding type: research
Funder scheme: ["TOP subsidies"]
Start date: 2017-05-01
End date: 2023-03-01
Investigator: dr. S.J.L. van den Heuvel
Institution: Universiteit Utrecht
Funded outputs count: 0
Funder award ID: zonmw-91216058-24049
OpenAlex ID: G6803884071