Searching for a cell-based therapeutic tool for haemophilia A within the embryonic/foetal liver and the aorta-gonads-mesonephros region



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Serrano, Luis J. and Cañete, Ana and García Leal, Tamara and Tomás Gallardo, Laura and Flores, Ana I. and Torre, Paz de la and Liras, Antonio and Sánchez, María José (2018) Searching for a cell-based therapeutic tool for haemophilia A within the embryonic/foetal liver and the aorta-gonads-mesonephros region. Thrombosis and Haemostasis, 118 (8). pp. 1370-1381. ISSN 0340-6245

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The development of new strategies based on cell therapy approaches to correct haemophilia A (HA) requires further insights into new cell populations capable of producing coagulation factor VIII (FVIII) and presenting stable engraftment potential. The major producers of FVIII in the adult are liver sinusoidal endothelial cells (LSECs) and in a lesser degree bone marrowderived cells, both of which have been shown to ameliorate the bleeding phenotype in adult HA mice after transplantation. We have previously shown that cells from the foetal liver (FL) and the aorta-gonads-mesonephros (AGM) haematopoietic locations possess higher LSEC engraftment potential in newborn mice compared with adult-derived LSECs, constituting likely therapeutic targets for the treatment of HA in neonates. However, less is known about the production of FVIII in embryonic locations. Quantitative polymerase chain reaction and Western blot analysis were performed to assess the relative level of FVIII production in different embryonic tissues and at various developmental stages, identifying the FL and AGM region from day 12 (E12) as prominent sources of FVIII. Furthermore, FL-derived VEcadþCD45- Lyve1þ/ endothelial/endothelial progenitor cells, presenting vascular engraftment potential, produced high levels of F8 ribonucleic acid compared with CD45þ blood progenitors or Dlk1þ hepatoblasts. In addition, we show that the E11 AGM explant cultures expanded cells with LSEC repopulation activity, instrumental to further understand signals for in vitro generation of LSECs. Taking into account the capacity for FVIII expression, culture expansion and newborn engraftment potential, these results support the use of cells with foetal characteristics for correction of FVIII deficiency in young individuals.

Item Type:Article
Uncontrolled Keywords:Foetal liver; AGM; Factor VIII; Haemophilia therapy; Newborn; Transplantation; LSEC ► LSEC
Subjects:Medical sciences > Medicine > Hematology
Medical sciences > Biology > Biotechnology
ID Code:56596
Deposited On:02 Oct 2019 11:19
Last Modified:03 Oct 2019 08:44

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