Periodic Reporting for period 1 - STELLA (Nutrient regulation of intestinal stem cells – exploring a novel mechanism with relevance to aging)
Período documentado: 2022-03-01 hasta 2024-02-29
Enhancing our understanding of how nutrients regulate tissue balance is crucial for comprehending the health effects of nutrition, especially for aging individuals. This project seeks to uncover the influence of nutrient availability on stem cell aging, potentially promoting tissue maintenance processes and extending health span.
The aim of the research was to explore the function of a novel nutrient-dependent regulator in intestinal stem cells and its role in maintaining tissue homeostasis during aging. More specifically, it focused on the nutrient-dependent role of a chromatin-binding protein, namely PWP1, on the regulation of intestinal stem cells (ISCs) and their ability to adapt their proliferation and differentiation rate according to dietary changes and aging.
The aim of the research was to explore the function of a novel nutrient-dependent regulator in intestinal stem cells and its role in maintaining tissue homeostasis during aging. More specifically, it focused on the nutrient-dependent role of a chromatin-binding protein, namely PWP1, on the regulation of intestinal stem cells (ISCs) and their ability to adapt their proliferation and differentiation rate according to dietary changes and aging.
The whole project was performed with the Drosophila melanogaster model system, and mainly involved the study of fly intestine (midgut) under different dietary regimens and with different age groups.
My findings revealed regional variations in PWP1 expression within the fly midgut. In the posterior midgut, where ISCs are more active, PWP1 tends to be predominantly expressed in the nucleus of progenitor cells. Interestingly, the protein becomes inactive under starved conditions, indicating that its regulation depends on nutrient availability.
Manipulating PWP1 expression in the fly midgut has consequences for normal intestinal turnover. Specifically, overexpressing PWP1 in ISCs and their daughter cells increases cellular turnover, while inhibiting PWP1 prevents ISCs from differentiating into absorptive cells (enterocytes – EC).
These results show that PWP1 has a nutrient-dependent role in the regulation of ISC differentiation towards the adsorptive cell type. Remarkably, genetic inhibition of PWP1 in the midgut during aging significantly reduces organismal lifespan and, at the cellular level, it causes a near-complete block of intestinal turnover and a reduction in the number of progenitor cells, hindering their differentiation into ECs. Transcriptomics and chromatin-binding analysis in young flies highlighted the involvement of the Hedgehog pathway in PWP1-dependent ISC regulation, with PWP1 acting upstream Hedgehog.
Given that PWP1 was previously identified as downstream of the mTOR pathway, my latest data suggests PWP1 may serve as a molecular link between the mTOR and Hedgehog pathways in the nutrient-dependent regulation of intestinal homeostasis.
My findings revealed regional variations in PWP1 expression within the fly midgut. In the posterior midgut, where ISCs are more active, PWP1 tends to be predominantly expressed in the nucleus of progenitor cells. Interestingly, the protein becomes inactive under starved conditions, indicating that its regulation depends on nutrient availability.
Manipulating PWP1 expression in the fly midgut has consequences for normal intestinal turnover. Specifically, overexpressing PWP1 in ISCs and their daughter cells increases cellular turnover, while inhibiting PWP1 prevents ISCs from differentiating into absorptive cells (enterocytes – EC).
These results show that PWP1 has a nutrient-dependent role in the regulation of ISC differentiation towards the adsorptive cell type. Remarkably, genetic inhibition of PWP1 in the midgut during aging significantly reduces organismal lifespan and, at the cellular level, it causes a near-complete block of intestinal turnover and a reduction in the number of progenitor cells, hindering their differentiation into ECs. Transcriptomics and chromatin-binding analysis in young flies highlighted the involvement of the Hedgehog pathway in PWP1-dependent ISC regulation, with PWP1 acting upstream Hedgehog.
Given that PWP1 was previously identified as downstream of the mTOR pathway, my latest data suggests PWP1 may serve as a molecular link between the mTOR and Hedgehog pathways in the nutrient-dependent regulation of intestinal homeostasis.
The discovery of unforeseen data broadened the storyline beyond the singular function of a protein, extending it to include a more comprehensive mechanism. My most recent findings showing that PWP1 acts upstream of the Hedgehog pathway, and its role as a downstream element of the nutrient-sensing mTOR pathway, suggests PWP1 may serve as a molecular link between the mTOR and Hedgehog pathways in the nutrient-dependent regulation of intestinal homeostasis.
Early results from genetic manipulation experiments conducted on Drosophila, along with the use of Rapamycin to inhibit the mTOR pathway, revealed the activation of both PWP1 and Hedgehog, respectively. These findings seem to support the proposed hypothesis. Consequently, PWP1 is now positioned as a central player in a mechanism that extends beyond initial expectations, significantly enhancing the importance of my research in the scientific community.
The maintenance of tissue balance and overall organism health depends on the ability of stem cells to renew themselves and differentiate effectively. However, these features are gradually lost during aging, being the principal cause of the appearance of diseases and declining organ function. The resulting worsening of life quality also represents a substantial healthcare cost for society. Notably, nutrition plays a crucial role on the correct functioning of stem cells and therefore on tissue homeostasis and organismal health span. The access to a balanced diet and sufficient nutritional education is a privilege, which is not available for the entire human population. Advancing the current knowledge on nutrient regulation of tissue homeostasis will be a step forward in improving our understanding of the health effects of nutrition, with substantial societal relevance for the aging population. Hence, this research will have the potential of providing new insights on how the understanding of stem cell aging regulation in response to nutrient availability could ameliorate the process of both physiological and pathological tissue decline, with beneficial effects on health span.
Early results from genetic manipulation experiments conducted on Drosophila, along with the use of Rapamycin to inhibit the mTOR pathway, revealed the activation of both PWP1 and Hedgehog, respectively. These findings seem to support the proposed hypothesis. Consequently, PWP1 is now positioned as a central player in a mechanism that extends beyond initial expectations, significantly enhancing the importance of my research in the scientific community.
The maintenance of tissue balance and overall organism health depends on the ability of stem cells to renew themselves and differentiate effectively. However, these features are gradually lost during aging, being the principal cause of the appearance of diseases and declining organ function. The resulting worsening of life quality also represents a substantial healthcare cost for society. Notably, nutrition plays a crucial role on the correct functioning of stem cells and therefore on tissue homeostasis and organismal health span. The access to a balanced diet and sufficient nutritional education is a privilege, which is not available for the entire human population. Advancing the current knowledge on nutrient regulation of tissue homeostasis will be a step forward in improving our understanding of the health effects of nutrition, with substantial societal relevance for the aging population. Hence, this research will have the potential of providing new insights on how the understanding of stem cell aging regulation in response to nutrient availability could ameliorate the process of both physiological and pathological tissue decline, with beneficial effects on health span.