| dc.description.abstract | As a standard treatment for many life threating diseases including leukaemia, bone marrow failure and auto-immune diseases, haematopoietic stem cells transplantation (HSCT) is often the only cure. There are three main sources of haematopoietic stem cells (HSCs): Bone marrow (BM), mobilised peripheral blood (PB), and umbilical cord blood (UCB/CB). Umbilical cord blood transplant represents a potentially unlimited source of HSCs, however, the limited number of total mononucleated cells including HSCs per unit of CB is a major challenge in its widespread use in HSCT. In order to unlock the potential of CB HSCs in transplantation, we need to investigate the mechanisms driving self-renewal and ex-vivo expansion. Endoplasmic reticulum (ER) is a continuous membrane system that provide an interconnected network for cellular regulation, and upon stress it can increase its membrane surface to upload more proteins. ER stress can be activated by hypoxia, oxidative stress, and infections. It responds through three main arms: PERK, IRE1 and ATF6 to suppress protein translation, increase protein folding-capacity, induce mRNA decay and when stress is not rescued it triggers apoptosis. Emerging evidence shows that ER stress contributes to HSCs fate. We believe unveiling the functions of the different ER pathways and their role in protein translation in HSCs will open new ways and strategies to expand CB ex-vivo. Here we used different ER stress modulators in CB CD34+ cells to understand how they could impact the maintenance and expansion of HSCs. Our study revealed that the core blood Lin- CD34+ CD38- population with larger ER volume are enriched with haematopoietic stem cells (Lin- CD34+ CD38- CD90+ CD45RA- CD49f+ HSCs). By optimising an ER staining probe on live cells, it has allowed us to dichotomise population based on the size of ER, and to further characterise endoplasmic reticulum’s role in CB HSCs by molecular (sc-RNAseq) and functional (colony forming and Long-term culture-Initiating cells) analyses. | en_US |
