Stem cells Architectures: How the spatial interactions of hematopoietic and mesenchymal stem cells regulate their polarity and division. – STAR

The goal of our project is to tackle two major challenges in hematopoeitic stem cell (HSC) research and cell therapy, which are (i) understanding the complex and multiple interactions of HSC with their physiological niches that control their self-renewal and differentiation (ii) designing and generating artificial niches in order to spawn and expand HSC and progenitors of interest for therapeutic applications.
Human HSC, paradigmatic of stem cell biology, are essential to maintain hematopoietic lineages homeostasis throughout life and have major potentials for treatment for haematological diseases. To maintain a tight balance between self-renewal and differentiation in time, HSC have the ability to divide either symmetrically or asymmetrically, and generate either similar daughter cells or cells of distinct identities and fates. Cell division asymmetry relies on cell cytoskeleton-dependant processes, i.e. cells polarization and mitotic spindle positioning, that lead to unequal partition of cell-fate determinants between the daughter cells, to cell daughter positioning in distinct micro-environments that trigger in turn distinct cell identities.
In vivo, vertebrate HSC are homed in distinct niches within the bone marrow, located respectively close to the mineralized matrix and around soft blood vessels. In these niches complex and specific combinations of extrinsic cues govern HSC quiescence or proliferation, self-renewal and/or differentiation. Cell-cell interactions are one of these parameters. In particular, HSC have been shown to interact with mesenchymal stem cells (MSC). HSC remain quiescent when associated to MSC in the endosteal niche, while they switch to an active state when contacting MSC in the perivascular niche. In addition, we and others have shed light on the importance of geometrical and physical niche properties on HSC and MSC biology using physical approaches and micro-fabrication technologies.
(i) The central role of cytoskeleton in mechano-transduction, extra cellular matrix signalling, asymmetric cell divisions has been elucidated in many biological systems, but remains poorly investigated in HSC self-renewal an differentiation processes. (ii) How bone marrow niches provide spatial information to MSC and HSC, direct their polarity, orient their division and thereby regulate the differentiation of daughter cells is currently not understood and of paramount importance to understand tissue homeostasis and regeneration.
Answering these questions is crucial for the development of culture-based systems recapitulating the mechanisms at play in the niche and supporting the expansion of HSC and MSC either with stemness maintenance or with monitored differentiation and propagation of specific differentiated cells of interest for transplantation purposes. Our project will investigate cytoskeleton-dependent mechanisms integrating physical and biochemical cues of the bone marrow niches and controlling cell polarization, asymmetric divisions and eventually distinct cell fates in human MSC and HSC. We also aim to address those mechanisms in the presence of endothelial cells and osteoblasts, which represents crucial cell type in the bona marrow niche. We then plan to design and engineer artificial niches with fine-tuned physical and biochemical properties in order to improve the production rate and quality of stem cells and progenitors routinely used for cell therapy. To do so we will couple micro-fabrication approaches, stem cell biology, quantitative live imaging that represent the respective the fields of expertise of the two partners of our consortium.