Extracellular vesicles mediated communication in the aging bone marrow
Within the bone marrow (BM), the hematopoietic system is responsible for the continuous replenishment of the different blood components. During aging, the hematopoietic stem cells (HSCs) undergo a series of changes that ultimately lead to reduced functionality. This results in unbalanced hematopoiesis that contributes to a number of age-associated pathologies, including immune senescence and chronic inflammation.
Decline of the homeostasis of HSCs with aging is the result of both alterations at cell intrinsic level and alterations in the crosstalk between HSCs and cells of the BM microenvironment (BMM). Extracellular vesicles (EVs) are particles that facilitate the exchange of very complex messages across cells. According to recent observations, EVs are an important component of the senescent-associated secretory phenotype (SASP) which itself is a distinctive secretory profile specific of senescent cells. While transient senescence is considered beneficial for the maintenance of the homeostasis of a tissue, chronic senescence has been associated with the development of age-associated pathologies.
In this project, we propose to characterize changes in EV shedding and composition that might occur when the cells of the BMM acquire a senescent phenotype and to investigate the contribution of these EVs to aging of the hematopoietic system, unbalanced hematopoiesis . The results obtained will provide useful insight on how EV mediated communication contributes to the aging of the hematopoietic system and whether this process can be modified to achieve resilience to aging.
Mentor: Univ.-Prof. Dr. med. Wolfram Ruf, Center for Thrombosis and Hemostasis (CTH)
Publications:
1. Karantanou C., Minciacchi V.R., Kumar R., Zanetti C., Tascher G., Tertel T., Covarrubias-Pinto A., Bankov K., Divieti-Pajevic P., McEwan D.G., Giebel B., Münch G., Dikic I., Krause D.S. “Impact of mesenchymal stromal cell-derived vesicular cargo on B-cell acute lymphoblastic leukemia progression.” Blood Adv. 2023 Apr 11;7(7):1190-1203.
2. Zanetti C., Kumar R., Ender J., Godavarthy P.S., Hartmann M., Hey J., Breuer K., Weissenberger E.S., Minciacchi V.R., Karantanou C., Gu Z., Roberts K.G., Metzler M., Stock W., Mullighan C.G., Bloomfield C.D., Filmann N., Bankov K., Hartmann S., Hasserjian R.P., Cousins A.F., Halsey C., Plass C., Lipka D.B., Krause D.S. “The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.” Blood. 2021 Nov 11;138(19):1870-1884.
3. Yekula A.*, Minciacchi V.R.*, Morello M., Shao H., Park Y., Zhang X., Muralidharan K., Freeman M.R., Weissleder R., Lee H., Carter B., Breakefield X.O., Di Vizio D., Balaj L. “Large and small extracellular vesicles released by glioma cells in vitro and in vivo.” J Extracell Vesicles 2019 Nov 27;9(1):1689784. *Equally contributing authors.
4. Minciacchi V.R., Spinelli C., Reis-Sobreiro M., Cavallini L., You S., Zandian M., Li X., Chiarugi P., Adam R.M., Posadas E.M., Viglietto G., Freeman M.R., Cocucci E., Bhowmick N.A., Di Vizio D. “Prostate fibroblast reprogramming induced by large oncosomes is mediated by MYC.” Cancer Res. 2017 1;77(9):2306-2317.
5. Vagner T.*, Spinelli C.*, Minciacchi V.R., Balaj L., Zandian M., Conley A., Zijlstra A., Freeman M.R., Demichelis F., De S., Posadas E.M., Tanaka H., Di Vizio D. “Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma.” J Extracell Vesicles 2018 Aug 7;7(1):1505403. *Equally contributing authors.
Further information: will follow soon