22 June 2022

How do cells control their fate? A task for CLASP2!

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In a joint effort between researchers of the groups of Niels Galjart (Erasmus MC Rotterdam) and Catherine Robin (Hubrecht Institute-KNAW), the microtubule-associated protein CLASP2 was found to safeguard the properties of hematopoietic stem cells, blood stem cells, throughout the development of fish and mice. These findings were published in Cell Reports on Tuesday 14th of June.

Life relies on blood stem cells
Blood stem cells or hematopoietic stem cells (HSCs) are at the foundation of the entire blood system. HSCs comply with the constant need for short-lived blood cell types throughout life without exhaustion, thanks to two major properties: multipotency (production of all blood cells) and self-renewal (production of new HSCs). In all vertebrates, HSCs first originate during embryonic life. Special cells, named hemogenic endothelial cells, are incorporated in the wall of the aorta in all embryos. These cells have the capacity to change their fate to progressively become HSCs. For this purpose, hemogenic endothelial cells detach from the wall of the aorta and progressively acquire a round shape and the properties of HSCs via a maturation process. These crucial events start in the aorta and continue in the fetal liver after the cells have migrated there. When fully mature, HSCs proliferate to form the pool of adult HSCs that will colonize the bone marrow where HSCs will reside for the entire life of an individual.

A long and complex journey
Before HSCs become fully functional, they must travel throughout different organs of the body where they respond to a myriad of signals during embryonic, fetal and adult life. To successfully complete this journey, HSCs rely on their ability to dynamically change their shape, sense their surrounding environment, migrate, and interact with cells to attach/detach in various tissues. In turn, these processes depend on the proper (re-)organization of the cytoskeleton, the complex and dynamic network of protein filaments present in the cytoplasm of all cells. Part of these filaments are microtubules (MT) that help cells to maintain their shape and internal organization (e.g., protein transport), and provide mechanical support for essential functions like division and movement. To function, the MT network needs to rapidly assemble and disassemble, a process highly controlled by MT-associated proteins such as CLASP2. Surprisingly, no studies have explored MT function in embryonic/fetal hematopoiesis, although pathway analyses of multi-dimensional sequencing have highlighted the potential involvement of cytoskeleton regulation, organization, and biogenesis in hematopoietic tissues of mouse and zebrafish embryos.

CLASP2 safeguards blood stem cell properties
HSCs express a large variety of cell surface receptors (e.g., c-Kit) that are associated with acquisition of self-renewal and multipotent properties. Correct expression of these receptors depends on a delicate balance between cell surface trafficking, recycling, and degradation and is in part controlled by the MT network and Golgi apparatus, whose roles have hardly been explored during embryonic/fetal hematopoiesis in vivo. By using both mouse and zebrafish, the researchers found that HSCs deficient for Clasp2 are not endowed with self-renewing capacity and undergo premature differentiation into more lineage-committed blood cell types. Ultimately, this leads to the depletion of the HSC pool. The deficiency in self-renewal in HSCs lacking Clasp2 is linked to impaired recycling of the HSC receptor c-Kit to the plasma membrane, due to a defective Golgi network and increased lysosomal degradation. These results suggest that a c-Kit expression above a certain threshold (rather than a binary absence or presence) is required for the acquisition and maintenance of HSC properties. CLASP2 appears to be a key player to achieve a proper c-Kit expression and signaling balance. Modulating the expression of key receptors such as c-Kit is an interesting concept to explore whether the generation and maintenance of functional HSCs could be improved in vitro.

CLASP2 safeguards hematopoietic stem cell properties during mouse and fish development. Anna Klaus, Thomas Clapes, Laurent Yvernogeau*, Sreya Basu*, Bart Weijts*, Joris Maas, Ihor Smal, Niels Galjart and Catherine Robin. Cell Reports 2022.
DOI: https://doi.org/10.1016/j.celrep.2022.110957
*These authors contributed equally

Image Catherine Robin



Catherine Robin is group leader at the Hubrecht Institute and is also affiliated with the UMC Utrecht