Periodic Reporting for period 4 - StemCellHabitat (Metabolic and Timed Control of Stem Cell Fate in the Developing Animal)
Berichtszeitraum: 2022-08-01 bis 2024-07-31
Stem cells are undifferentiated cells capable of self-renewing and differentiating into specialized cell types, playing an essential role in organismal development, tissue homeostasis, and repair. Stem cells thus harbor great potential for regenerative medicine, but significant gaps remain in our understanding of the mechanisms that govern stem cell fate decisions and their proliferation. This project aimed to study how stem cells are regulated during animal development according to their spatial, temporal, and metabolic identity, using Drosophila melanogaster as a model system. The fruit fly, a relatively simple organism with well-characterized stem cell populations, offers a powerful platform to dissect the mechanistic details of stem cell regulation and its impact on tissue development and disease.
Using a multidisciplinary approach that combines genetics, cell type/age sorting, multi-omics analysis, fixed and 3D live stem cell imaging, and metabolite dynamics, this project investigated how stem cells are regulated in the developing animal.
Using a multidisciplinary approach that combines genetics, cell type/age sorting, multi-omics analysis, fixed and 3D live stem cell imaging, and metabolite dynamics, this project investigated how stem cells are regulated in the developing animal.
Notable findings include the discovery of metabolic heterogeneity in Drosophila brain tumors, which affects lactate production and tumor progression (Garcez et al., under preparation). We also uncovered the role of amino acid transporters in brain tumor growth (Rebelo et al., Cell Mol Life Sci, 2023) and identified a novel mechanism controlling neurotransmitter gene expression during neuron maturation. In Marques et al. (2024, PLoS Biology), we show that early-born neurons undergo a three-phase maturation process in which neurotransmitter gene transcription precedes translation, which occurs later in coordination with developmental timing. Our research also highlighted the importance of one-carbon metabolism in neuroepithelial development (Silva et al., Development, 2024). We further found that developmental cues, particularly those from hormone signaling, are critical for instructing neural stem cells to stop proliferating, thus terminating neurogenesis at the appropriate time. Additionally, we explored how the germ stem cell fate is coordinated with mitochondrial activity and dynamics. We discovered that mitochondrial dynamics in the Drosophila ovary regulate germ stem cell number, cell fate, and female fertility (Garcez et al., Front Cell Dev Biol, 2021). The findings were also disseminated at national and international conferences.
In addition to these results, the project led to the development of innovative tools, including FLYNC, a software that uses transcriptomic data to identify novel long non-coding RNAs (lncRNAs) in Drosophila (dos Santos et al., BioRxiv, 2024). Overall, these results and innovations are expected to significantly advance stem cell and cancer research.
In addition to these results, the project led to the development of innovative tools, including FLYNC, a software that uses transcriptomic data to identify novel long non-coding RNAs (lncRNAs) in Drosophila (dos Santos et al., BioRxiv, 2024). Overall, these results and innovations are expected to significantly advance stem cell and cancer research.
This project has made significant advances beyond the current state of the art by uncovering new mechanisms in stem cell regulation, particularly the role of metabolic and mitochondrial dynamics in stem cell fate and neurogenesis. We have identified novel hormonal cues that govern the termination of neurogenesis, a key process not fully understood in current models. Additionally, the development of FLYNC software, which uses transcriptomic data to discover novel long non-coding RNAs in Drosophila, provides an innovative tool for advancing research in gene regulation and stem cell biology. These breakthroughs offer new insights into the metabolic control of stem cells and cancer, positioning this work at the forefront of stem cell and developmental biology research.