Transcriptional Regulation of the Hemogenic Endothelium

Speaker Name: 
Carlos Lizama
Speaker Title: 
Postdoctoral Scholar
Speaker Organization: 
UCSF
Start Time: 
Thursday, March 7, 2019 - 12:00pm
End Time: 
Thursday, March 7, 2019 - 1:00pm
Location: 
Biomed 200
Organizer: 
Camilla Forsberg

Hematopoietic stem cells (HSC) are generated during embryogenesis from specialized vascular beds termed hemogenic endothelium (HE), including the aortic endothelium of the aortic-gonado-mesonephros (AGM) region. In the aorta, pre-HSCs are organized in clusters attached to the vascular endothelium. Changes in cell fate and identity are essential for endothelial-to-haematopoietic transition (EHT), an embryonic process that generates the first adult populations of HSCs from hemogenic endothelial cells. The concept of endothelial-derived HSCs has broad clinical implications as it may open new avenues for in vitro blood production. However, the hemogenic capacity of the endothelium is transient and we do not know how distinct endothelial and haematopoietic fates are parsed during the transition. During this seminar, I will show that genes required for arterial Identity function later to repress haematopoietic fate. Temporal genetic loss of arterial genes Sox17 and Notch1 during EHT results in increased production of haematopoietic cells due to loss of Sox17-mediated repression of haematopoietic transcription factors (Runx1 and Gata2). In the same line I will talk about the role of SMAD4 in the HSC maintenance during embryogenesis. The TGF signaling pathway has a pivotal role in both arterial specification and HSC formation. Previous endothelial SMAD4 loss-of-function studies in mice using a Tie2cre have demonstrated a critical role of this protein in the EHT, with notable phenotypes of increased cluster formation and embryonic lethality at E10.5. In order to bypass the early lethality seen in other studies, we used an inducible arterial Cre to delete SMAD4 to evaluate the contribution of the TGF signaling pathway to later EHT events, as well as HSC migration, and colonization of adult hematopoietic organs. We noted embryonic lethality between E13.5-E17.5 in animals with SMAD4 loss of function in arterial endothelial cells. The mutants exhibited decreased HSC numbers, enlarged fetal livers, erythropoiesis defects, and the inability to engraft adult recipients. In addition, we evaluated the deletion of SMAD4 using NG2cre which is expressed within the sub-aortic mesenchyme during EHT. The mutant mice did not exhibit any hematopoietic abnormalities and survived until adult life. These data suggest that the TGF signaling pathway in arterial endothelial cells is critical for definitive hematopoiesis while other non-endothelial sources of TGF do not contribute to the endothelial to hematopoietic transition or definitive hematopoiesis.

 

Bio: Dr. Lizama grew up in Chile and attended the Pontificia Universidad Católica de Valparaiso, graduating with a bachelor in Biochemistry. He subsequently trained as a Ph.D Msc in Physiology at the Pontificia Universidad Católica de Chile in Santiago. During his Ph.D, he studied the mechanism of germ cell apoptosis that regulates spermatogenesis during postnatal testis development, the role of tissue matrix interactions in germ cells with a specific focus on ADAM metalloproteases and the pharmacological impact of cancer therapeutics and environmental toxins on germ cell maintenance and spermatogenesis. As a Postdoctoral Fellow in the Laboratory of Ann Zovein at UCSF, he focuses in the hematovascular system. Specifically, he described the role of Sox17 and Notch1 during the endothelial to hematopoietic transition (EHT) in the dorsal aorta during embryogenesis. He was awarded with a K99/R00 grant to start  independent research. During the K99 phase, he has been studying the mechanisms of arterial-vein specification during early stage of embryo development. In addition, he has begun to investigate the role of epigenetic control of hemogenic endothelium.