About the Project
In the skeletal system, vasculature plays a central role in the maintenance of microenvironments (niches) required for regulating osteogenesis and hematopoiesis. Apart from supplying nutrients, vasculature provides a number of inductive signals so-called angiocrine factors to regulate the specific vascular niche. Skeletal ageing characterized by decreased osteogenesis and deregulated hematopoiesis is associated with the changes in the bone vasculature. However, the relation between blood vessels and skeletal ageing is not known.
We have recently identified a structurally and functionally distinct vessel subtype in bone, which mediates developmental and regenerative angiogenesis. These vessels termed, ‘type-H’ due to the high expression of specific markers, physically associate with osteoprogenitors and generate an active niche for the cells of osteoblast lineage. The abundance of type-H endothelium gradually declines in adult and ageing mice as compared to juvenile mice, which provides a compelling explanation for the age-associated bone loss seen in rodents and humans. Reactivation of type-H endothelium in aged mice resulted in increased osteoprogenitors and improved bone-mass. Similarly, type-H vessels generate a specific microenvironment for the maintenance of hematopoietic stem cells in bone. We use mouse as a model system to investigate how blood vessels mediate these age-related changes in the bone marrow niche.
Using mouse genetics, we will specifically manipulate endothelial cells to understand the changes in mesenchymal and hematopoietic compartment of the bone marrow vascular niche. This project involves a powerful combination of novel approaches such as advanced 3D imaging, intra-vital imaging and cell-specific inducible mouse genetics to investigate the function of blood vessels in bone. The study will not only unravel the mechanism behind the cause of skeletal ageing, but has the potential to identify novel therapeutic strategies for managing age-related bone and blood diseases.
References
1. Ramasamy SK, Kusumbe AP, Itkin T, Gur-Cohen S, Lapidot T, Adams RH (2016) Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals. Annu Rev Cell Dev Biol. 2016
2. Ramasamy SK, Kusumbe AP, Adams RH (2015) Regulation of tissue morphogenesis by endothelial-derived signals. Trends Cell Biol. 52: 148-157.
3. Ramasamy SK*, Kusumbe AP*, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507: 376-380.
4. Kusumbe AP*, Ramasamy SK*, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507: 323-328.
* Equal contributions
5. Kusumbe AP, Ramasamy SK, Itkin T, Mäe MA, Langen UH, Betsholtz C, Lapidot T, Adams RH (2016) Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532:380-384.
6. Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, Ledergor G, Jung Y, Milo I, Poulos MG, Kalinkovich A, Ludin A, Kollet O, Shakhar G, Butler JM, Rafii S, Adams RH, Scadden DT, Lin CP, Lapidot T