Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo (153.5)

Abstract

Abstract Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells is suboptimal in these hosts. We hypothesized that this defect was due to reduced cross-reactivity of mouse cytokines on the human receptor. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. We generated RAG2-/-γc-/- mice in which we replaced the gene encoding mouse TPO by its human homologue, and we transplanted human CD34+ cells in these recipients. Homozygous humanization of TPO (TPOh/h) led to increased levels (higher than 80%) and longer maintenance (more than 6 months) of human cell engraftment in the bone marrow of the hosts. Multilineage differentiation of hematopoietic cells was also improved, with an increased ratio of myelomonocytic verus lymphoid lineages. Moreover, maintenance of human stem and progenitor cells was improved : we observed a significant increase in the fraction of human Lin-CD34+CD38-CD90+CD45RA- cells in TPOh/h compared to control recipients; and CD34+ cells purified from TPOh/h primary recipient had a significantly increased capacity to efficiently engraft secondary recipients. Therefore, RAG2-/-γc-/- TPO-humanized mice represent a novel model to study human hematopoiesis in vivo.