Investigating irradiation damage to haematopoietic niches in the spleen

Haematopoietic stem cell transplantation (HSCT) is used to treat patients with blood disorders such as leukaemia. Intravenous HSCT allows cells to home to the bone marrow niche and initiate long-term haematopoietic reconstitution. However, HSC can also home to extramedullary organs such as the spleen. Under these circumstances, the spleen possesses the capacity to support extramedullary haematopoiesis (EMH) and immune cell production. This secondary function of the spleen could be targeted to enhance early haematopoietic reconstitution after HSCT. To ensure the success of HSCT, patients must first be conditioned to clear niche space for transplanted HSC to engraft. Radiotherapy used to condition HSCT recipients not only causes myeloablation but also results in non-specific damage to multiple tissues including bone marrow and stem cell niches. It is known that sinusoidal endothelial cells in the bone marrow are both important HSC niche regulators and are damaged following irradiation. In the murine spleen, Scf-expressing endothelial cells and Tcf21+ cells have been shown to form perisinusoidal niches in the red pulp for HSCs to reside in. This project investigates whether damage caused by lethal irradiation extends to the spleen, by examining stromal and endothelial cells using markers such as CD105, MAdCAM-1, MECA-32, VCAM-1, PDGFRβ and CD31 in order to resolve multiple vascular and mesenchymal structures including splenic HSC niches. If the stromal niches regulating extramedullary haematopoiesis during the early period of haematopoietic recovery can be better understood, it may lead to therapies which accelerate immune reconstitution and ultimately lessen rates of transplant-associated mortality.