On Tuesday 19 May 2020, K.J.G. Kenswil will defend his PhD dissertation, entitled: ‘Niche Contributions to Bone Marrow (Re)generation’.
Chemotherapy is one of the most common treatments for cancer patients. However, a possible adverse effect of chemotherapy is bone marrow (BM) damage, including the disruption of blood cell production (hematopoiesis). The focus of the work presented in this thesis is how the BM microenvironment (the hematopoietic niche), in particular endothelial cells (ECs), contributes to BM recovery after chemotherapy-induced injury in humans.
Recent work in mice attempting to identify the cellular and molecular factors underlying hematologic recovery revealed that ECs can facilitate BM regeneration by expressing distinct signaling molecules (“angiocrine” factors). Furthermore, newer studies have identified and characterized a specialized subset of these ECs in mice (type H-endothelium) that actively link blood vessel development (angiogenesis) to bone formation (osteogenesis). However, the relevance of these findings for humans remains largely unknown due to lack of studies focusing on humans.
The findings presented in this thesis reveal the existence of a human EC subtype associated with regeneration and BM formation (dubbed hREC), reminiscent of the type H-endothelium of mice. Interrogation of the gene expression profile of hRECs lead to the discovery of interleukin-33 (IL-33) as a novel angiocrine and anabolic niche factor. In addition, we found that endothelial-derived mesenchymal (stemlike) cells can contribute to hematopoietic niche formation in mammals during fetal development through the process of endothelial-to-mesenchymal transition (EndMT). In this context IL-33 is identified as a novel and strong mediator of EndMT. Lastly, the results in this thesis also provide insights on the recovery (kinetics) of immune cells following chemotherapy-induced injury.
The PhD defences will not take place publicly in the Senate Hall or Professor Andries Queridoroom due to the coronavirus. The candidates will defend their thesis online.