Hematopoietic stem cells (HSCs) are a critical and rare population of cells that can self- renew extensively and produce all blood cell lineages. HSCs are maintained and regulated throughout life by extrinsic regulation; disruption of this regulation can lead to loss of HSCs and hematopoietic failure. Thus, understanding HSC extrinsic regulatory mechanisms has important therapeutic implications. Thrombopoietin (TPO) is a hematopoietic cytokine that is canonically understood as a driver of megakaryocyte proliferation and platelet production, but has also been shown to be required for HSC maintenance. However, since TPO is made in the bone marrow, the liver and other tissues, the relative contributions of local and systemic TPO to HSC function are still unknown. This project aims to characterize the in vivo role of TPO in HSC biology by use of two novel mouse models that allow identification of TPO+ populations in the bone marrow, and conditional deletion of Tpo from select tissues. The experiments in this proposal will define the role of TPO in HSC biology, and have major implications for clinical therapies that take advantage of our novel understanding of how HSC regulation is balanced between local and systemic factors.
This project proposes to elucidate how the body regulates hematopoietic stem cell function via thrombopoietin signaling. Using novel mouse models, we will show which tissues are the key sources of thrombopoietin that maintain hematopoiesis. The findings from our project will have important implications for development of clinical therapies that support hematopoietic function in bone marrow disease and transplant.
| Decker, Matthew; Leslie, Juliana; Liu, Qingxue et al. (2018) Hepatic thrombopoietin is required for bone marrow hematopoietic stem cell maintenance. Science 360:106-110 |
| Sarkaria, Shawn M; Decker, Matthew; Ding, Lei (2018) Bone Marrow Micro-Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies. Bioessays 40: |
