Metabolic regulation of stem cells in the bone marrow niche
In the Plenary session on Sunday Dr Tsvee Lapidot (Weizmann Institute of Science, Rehovot, Israel) discussed recent work on normal and leukemic hematopoiesis in the bone marrow (BM) microenvironment. In this compartment, hematopoietic stem progenitor cells (HSPCs) are bound to BM stromal cells, and are kept in a quiescent, low metabolic state with low levels of reactive oxygen species (ROS) and nitric oxide (NO). “This is the reason why HSPCs are chemotherapy resistant”, Lapidot explained.
The adhesion interactions are dynamic, allowing for blood cell production on demand. Pro-inflammatory cytokines, such as thrombin, induce secretion of the chemokine CXCL12. The HSPCs then upregulate CXCR4, the receptor for CXCL12, stimulating stem cell migration into the blood stream, proliferation and differentiation. In this state, the stem cells are no longer protected from chemotherapy.
In order to remain undifferentiated and chemotherapy resistant, HSPCs must keep their ROS levels low by transferring excess ROS to BM stromal cells via Cx43 gap junctions. Possibly HSPCs even transfer mitochondria, a model that Lapidots group is currently investigating.
He discussed how other cell types in the microenvironment also participate in maintaining quiescence of HSPCs and chemotherapy resistance. Increased permeability of the endothelial blood-bone marrow barrier leads to enhanced differentiation and egress to the circulation. Expression of the anti-coagulant receptor EPCR is important for keeping NO levels low. Thrombin induces NO generation and shedding of EPCR, allowing HSPCs to proliferate, differentiate, and egress. In mouse models of AML, reducing ROS or NO preserved normal stem cell function and improved treatment response.