Human ossicles for iPS-HSC development and Leukemia modeling

The emergence of induced pluripotent stem cells (iPS) has offered unprecedented opportunities in developmental biology and regenerative medicine. Generated from patient cells, iPS maintains their genetic features, allowing deciphering healthy or pathological processes in a personalized fashion. Applied to hematopoiesis, this technology holds enormous promises towards generating transplantable hematopoietic stem cells (HSCs), or modeling hematological malignancies. If iPS-derived hematopoietic cells can be obtained in vitro, yet fully functional iPS-HSCs could not be produced. Similarly, iPS blood cells generated from B cell leukemic patients fail at recapitulating the associated disease-specific patterns. This calls for the exploration of new tools capable of improving the formation and maturation of iPS blood populations. 

Inspired from the fetal hematopoietic development in bones, we here propose the exploitation of the human ossicle (hOss) technology. These hOss consist in miniaturized bone organs composed of a human mesenchymal niche shown to support hematopoiesis. We hypothesize that the hOss can support the engraftment and maturation of healthy iPS-HSCs, but also provide a platform for modeling B-cell malignancy using iPS derived blood cells. If successful, this project bears high relevance for the modeling of human healthy and malignant hematopoiesis and will prompt the development of innovative regenerative therapies.

IGNITE Fellow - Sara González Antón

Sara González Antón completed her PhD in London, where she investigated the effects of acute myeloid leukaemia (AML) and chemotherapy on haematopoietic stem cells and the bone marrow niche. Her work led to the identification of potential targets to enhance bone marrow recovery following treatment.

Nearly two years ago, she moved to Sweden to begin her postdoctoral research in Paul Bourgine’s lab. Since then, her work has focused on studying CAR T cell (CAR Tc) therapy in the context of AML using the humanised ossicle model. While CAR T cell therapy has shown great promise for several haematological malignancies, it has not yet been successful in treating AML. By employing the humanised ossicle model, she explores the role of the human bone marrow niche, particularly mesenchymal stem/stromal cells, in the limited efficacy of CAR Tc therapy in AML, with the aim of identifying potential targets to improve therapeutic outcomes.

Although induced pluripotent stem cell (iPSC)-derived haematopoietic stem cells (HSCs) hold significant promise for modelling blood malignancies, several challenges remain. In Charlotta Böiers’ lab, a paediatric B-ALL model has been developed using iPSC-derived HSCs. However, these cells show minimal or no engraftment and development in vivo when transplanted into conventional mouse models. This project aims to investigate the influence of the human bone marrow niche on the engraftment and progression of the B-ALL iPSC model, using the humanised ossicle platform developed in Paul Bourgine’s lab. Leveraging this model may help overcome the limitations associated with sample availability and collection, and ultimately deepen our understanding of the disease.

Main Principal Investigator

• Paul Bourgine

Co-supervisor

• Charlotta Böiers