Final Report Summary - STEMCHIP (Probing organ-level stem cell dynamics on a chip)
More than 30’000 patients with hematological malignancies greatly benefit from hematopoietic stem cell (HSC) transplants each year in Europe alone. However, availability of transplant material for afflicted patients, prognosis, and relapse-free survival are all hindered by the limited quantity of HSCs available for therapy. Despite several decades of research, HSC, arguably the best-characterized somatic stem cells, can hardly be cultured in vitro without undergoing rapid differentiation. This is largely due to our poor understanding of the mechanisms that regulate HSC fate in response to cues from their microenvironmental ‘niche’, and the difficulty to unveil these mechanisms using existing experimental model systems. The only means to functionally characterize HSCs is their transplantation into irradiated mice to assess their long-term ability to generate blood. Although a powerful functional assay, transplantation is not well suited for gaining mechanistic insights on HSC behavior in mice, least of all in humans. Existing in vitro systems to study HSCs lack a functional niche and a systemic environment, and thus fail to provide insights into the physiological behaviors and dynamics of the stem cells. In the STEMCHIP project, we have developed novel in vitro culture approaches to begin to recapitulate tissue-level function in regulating HSC behavior. We have for example designed modular microfluidic systems comprising a niche compartment that mimics key anatomical, cellular and molecular characteristics of HSC niches that can be coupled to a fluidic network acting as a surrogate of the native circulation. Our approach should allow, for the first time, the in vitro modelling of dynamic physiological HSC processes such as the ‘homing’ of stem cells to the niche after transplantation, and the ‘mobilization’ of stem cells from the niche upon systemic stimulation.