Integrins Modulate Extracellular Matrix Organization to Control Cell Signaling during Hematopoiesis
This week we profile a recent publication in Current Biology from Rohan
Khadilkar (pictured above) in the laboratory of Dr. Guy Tanentzapf (below) at UBC.
Can you provide a brief overview of your lab’s current research focus?
Stem cells are essential for animal development and allow the maintenance and regeneration of tissues. Stem cells retain the capability to divide and to develop into many types of adult cells throughout the lifetime of an organism. The blood stem cells in humans and animals are particularly important for fighting infections as they produce the immune cells required to fight infection. A major project in our lab seeks to understand the mechanisms that regulate the activation of blood stem cells such that they produce immune cells upon infection. Our work focuses on the role played by the blood stem cells’ environment in regulating this transition. In particular we focus on the role of various cell junctions in shaping the signals that control stem cell behaviour. Our general model is that, in response to infection, the stem cell environment changes in very specific ways and that this induces the activation of blood stem cells. Understanding the mechanisms that induce blood stem cell activation upon infection will help us gain insight into what happens in diseases that affect the blood stem cell niche such as leukemia and autoimmune diseases.
What is the significance of the findings in this publication?
One of the best-characterised types of external cues that control stem cell behaviour is provided by the extra-cellular matrix (ECM). In particular, integrins, the main family of adhesion receptors that mediate cell-ECM adhesion in animals, have been implicated in diverse contexts as important regulators of stem cells. For example, during vertebrate hematopoiesis, integrins assist in the migration to, as well as the physical attachment of, hematopoietic stem cells to the niche. However, whether and how integrins are also involved in the signalling mechanisms that control hematopoietic stem cells remains to be resolved.
Our manuscript shows that integrins play a key role during fly hematopoiesis in regulating cell signals that control the behaviour of hematopoietic progenitors. Integrins regulate fly hematopoiesis directly, via integrin-mediated FAK signalling, and indirectly, by modulating ECM density. ECM density controls blood progenitor behaviour by influencing multiple signalling pathways, including bone morphogenetic protein (BMP) and Hedgehog (Hh). We show that integrins and ECM proteins are expressed in the fly hematopoietic organ — the lymph gland. Knockdown experiments show that integrins are required for regulating blood cell production and blood progenitor maintenance. Using long-term live imaging of intact cultured lymph glands from wildtype and integrin knockdown flies we show that integrins are not required for lymph gland integrity or to physically anchor progenitors in place. However, quantitative imaging and gain or loss of function approaches show that integrins modulate the density of the lymph gland ECM. Mutations that cause low ECM density exhibit ectopic blood cell differentiation and depletion of the progenitor pool. Genetic interaction studies and marker analysis show that modulation of ECM density downstream of integrins impacts both FAK and BMP signalling. Finally, we show that the induction of blood cell differentiation following infection requires a decrease in the density of the lymph gland ECM.
The implications of our work are substantial. We describe a potentially novel mechanism by which integrins can control the signalling milieu around stem cells. Specifically, we propose that by controlling the density of the ECM, integrins can simultaneously fine-tune multiple signalling pathways acting on stem cells within an organ. Moreover, given that association of the ECM and stem cells is a conserved feature of hematopoiesis, our work provides important insight into the mechanisms that control blood development and cellular immunity in animals.
What are the next steps for this research?
A major aim of our future studies is to gain further and more specific understanding of how infection remodels the ECM in order to control blood cell production.
This work was funded by:
Work in our lab is funded by grants from the Canadian Institute for Health Research and the Natural Science and Engineering Research Council of Canada.