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Research groups

Cell biology and Biotechnology

Dr María José Sánchez Sanz. CSIC
Development of the hemato-vascular system and stem cells
Dr María José Sánchez Sanz. CSIC
Principal Investigator

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Summary



A primary interest of our laboratory is to understand the events leading to blood formation, differentiation and homeostasis during development. We study the ontogenic relationship of blood and endothelial cells and their functional crosstalk; analyze the role of Notch1 in hemato-vascular differentiation; and explore the dynamics of vascular progenitor engraftment and repopulation. We address these questions in the mouse model using a combination of transgenic mice, cell culture, flow cytometry, image analysis and transplantation assays.
Studies in hematopoiesis have a direct impact in an important medical application: blood stem cell transplantation. Our studies should help to better understand the properties of different stem cell populations emerging during development; to discover new factors to expand them ex vivo; and  to identify vascular progenitors with potential to repopulate organ vasculature.

 


Laboratory focus: Fetal hematopoietic progenitors have superior blood engraftment competence compared with adult bone marrow. We showed in transplantation assays that fetal liver cells also posses enhanced vascular endothelial engraftment potential. Using donor cells from mice transgenic for the hemato/vascular stem cell leukaemia 3' enhancer (SCL-3'Enh) driving the human placental alkaline phosphatase (PLAP) reporter gene, high-level vascular chimeras were generated when SCL-3'EnhPLAP+ fetal liver cells were transferred into newborn receptor mice. Long-term lineage tracing and multicolour lineage analysis reveals PLAP+ vascular repopulated patches in the liver, heart and kidney. More recently, using FACS sorting, in vitro hemato/vascular differentiation assays and long term repopulation analysis, we have characterized different cell subsets that suggests a hemato-vascular lineage hierarchy unique to the fetal liver.

We have also determined using liver vascular repopulation as a model, that fetal derived endothelial cell grafts grow and stabilize over long term; induce endogenous hepatocyte proliferation; and occur in the absence of chemical conditioning of newborn receptor, allowing the generation of physiological organ specific vascular chimeras.

Another focus of the laboratory is to investigate the different role of Notch signaling in fetal, newborn and adult hematopoietic stem cells. Homing, proliferation, differentiation and up-regulation of Notch downstream genes have been evaluated in SCL3'Enh-NIC gain of function transgenic mice. We have established that, although hematopoietic stem cells from different developmental stages express Notch1, fetal and newborn stem cells are refractory to NIC activation, reflecting their heterogeneity. We are currently analyzing the effect of Notch1 conditional mutation in the fetal liver hemato-vascular populations.

Through detailed dissection of the hemato-vascular cell populations in the fetal liver and the analysis of the mechanisms of differentiation and engraftement we hope to further understand the diverse interaction levels of endotelial and hematopoietic stem cells and their contribution to sculpt the fetal liver niche for hematopoietic stem cells. We also intend to continue to develop and advance in the characterization of liver vascular quimeras, to address the role of endotelial vasculature in neonatal organogenesis, and to generate vascular related disease models.