MakingBlood: Engineering an integrated platform for generation of human blood stem cells from pluripotent sources

Life-saving blood cell replacement depends on voluntary donors. Availability is a challenge for specific groups, and 25% of patients needing blood stem cell transplants lack a compatible donor. The ideal alternative is clinical-scale production of Haematopoietic Stem Cells (HSC) from laboratory-maintained tissue-compatible sources, to provide an off-the-shelf source of blood cells. HSC are generated in the aorta/gonad/mesonephros region of the embryo, expand in the foetal liver, and are maintained in the bone marrow of adults. Current attempts to generate HSC in vitro do not consider the changing cellular, chemical, and physical characteristics of the different environments met by HSC in vivo from embryo to adult, and have been unable to reliably produce functional HSC. MakingBlood aims to establish a proof-of-concept platform for robust generation of human HSC from pluripotent stem cells by developing a self-organising gastruloid model of embryonic HSC generation without genetic manipulation, and successively recapitulating the natural foetal and adult HSC development environments. MakingBlood brings together an expert in HSC embryonic development, a national blood bank research director with expertise in adult HSC, an expert in molecular regulation of cell fate choices, and a bioengineer with expertise in mechanical and chemical integration for tissue production to deliver this breakthrough platform. By using state-of-the-art technology and multidisciplinary approaches, we will systematically detangle cellular, chemical, and physical properties of natural HSC generation, amplification and maintenance microenvironments, and iteratively identify essential elements that enable and promote HSC function. We will integrate key elements into modular scalable engineered niches to establish a HSC production platform, which can be developed as a bioreactor for on-demand blood production, and eventually replace donations as the clinical source of HSC and mature blood cells.