Periodic Reporting for period 2 - ReSinAge (Regeneration of Sinusoidal niches to preserve hematopoiesis after chemotherapy on Ageing)
Reporting period: 2022-09-01 to 2024-02-29
Cancer is a disease of the elderly and chemotherapy remains the mainstay of treatment. The benefits of chemotherapy include increased overall survival, improvement in quality of life, and palliation of symptoms. However, older patients are more susceptible to specific toxicities of chemotherapy, like myelosuppression and life-threatening neutropenia.
Among the tissues strongly affected by chemotherapy, the bone marrow sinusoidal endothelial cells constitute the most important supportive niche for aged hematopoietic stem cells function and for myelopoietic recovery in the elderly. Up to now, few data are available about how aged sinusoidal niches regenerate upon chemotherapy damage and whether it is possible to rejuvenate vascular endothelial stem cells and improve the regeneration of the old sinusoidal niche as an effective strategy to improve HSC function and prevent myelosuppression and life-threatening neutropenia in the elderly.
ReSinAge explores the possibility of improving the regenerative capacity of aged bone marrow endothelial cells as a target to enhance the hematopoietic recovery and increase the survival after chemotherapy in the elderly.
By combining several ground-breaking approaches ranging from single-cell sequencing, whole-mount bone marrow imaging, deep learning strategies for data analysis and integration, stem cell sorting techniques and specific mouse models, this research project will demonstrate that aging is not irreversible and that targeting the stem cell niche could represent an unprecedented innovative strategy to improve the regenerative capacity not only of hematopoietic stem cells.
Among the tissues strongly affected by chemotherapy, the bone marrow sinusoidal endothelial cells constitute the most important supportive niche for aged hematopoietic stem cells function and for myelopoietic recovery in the elderly. Up to now, few data are available about how aged sinusoidal niches regenerate upon chemotherapy damage and whether it is possible to rejuvenate vascular endothelial stem cells and improve the regeneration of the old sinusoidal niche as an effective strategy to improve HSC function and prevent myelosuppression and life-threatening neutropenia in the elderly.
ReSinAge explores the possibility of improving the regenerative capacity of aged bone marrow endothelial cells as a target to enhance the hematopoietic recovery and increase the survival after chemotherapy in the elderly.
By combining several ground-breaking approaches ranging from single-cell sequencing, whole-mount bone marrow imaging, deep learning strategies for data analysis and integration, stem cell sorting techniques and specific mouse models, this research project will demonstrate that aging is not irreversible and that targeting the stem cell niche could represent an unprecedented innovative strategy to improve the regenerative capacity not only of hematopoietic stem cells.
Up to now we have established several mouse lines to investigate the role of Jag2 expression in bone marrow endothelial cells and identify its relevance for the decline of endothelial niche support to HSC function with aging. Moreover, we have also established several mouse lines to investigate the role of Cdc42 overactivation in the regeneration of the bone marrow endothelial compartment and for the function of vascular endothelial stem cells. These experiments will eventually validate the specificity of the Cdc42-activity inhibitor CASIN to improve the regeneration of the endothelial compartment in the elderly. We have performed several studies on aging mice to optimize the CASIN treatment for HSC rejuvenation in vivo and we were able to extend murine healthspan and lifespan with this treatment. We are now focusing on refining the same CASIN treatment scheme to improve survival of aged mice after chemotherapy.
This research project and the data obtained so far demonstrate that aging is not irreversible and that targeting the stem cell niche could represent an unprecedented innovative strategy to improve the regenerative capacity of different somatic stem cells. We are providing proof-of-concept evidence that increasing the regenerative potential of endogenous aged somatic stem cells might indeed represent an important strategy for rejuvenating tissues and improving health- and lifespan in the elderly.