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Thromb Haemost 2018; 118(08): 1370-1381
DOI: 10.1055/s-0038-1661351
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Searching for a Cell-Based Therapeutic Tool for Haemophilia A within the Embryonic/Foetal Liver and the Aorta-Gonads-Mesonephros Region

Luis J. Serrano   *
1   Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
2   Department of Physiology, School of Biology, Complutense University of Madrid, Madrid, Spain
,
Ana Cañete   *
3   Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, Seville, Spain
4   Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
,
Tamara Garcia-Leal
3   Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, Seville, Spain
,
Laura Tomás-Gallardo
3   Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, Seville, Spain
,
Ana I. Flores
1   Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
2   Department of Physiology, School of Biology, Complutense University of Madrid, Madrid, Spain
,
Paz de la Torre
1   Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
,
Antonio Liras   **
1   Grupo de Medicina Regenerativa, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
2   Department of Physiology, School of Biology, Complutense University of Madrid, Madrid, Spain
,
María José Sánchez   **
3   Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, Seville, Spain
› Author Affiliations Funding This work was supported by the Spanish Ministry of Science and Technology Grant BFU2010–15801; Junta de Andalucia Research Funding Program PAI-BIO-295 and the Andalusian Association of Haemophilia ASANHEMO FV2016–20.
Further Information

Publication History

19 October 2017

07 May 2018

Publication Date:
10 July 2018 (online)

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Abstract

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 marrow-derived 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 VE-cad+CD45-Lyve1+/− endothelial/endothelial progenitor cells, presenting vascular engraftment potential, produced high levels of F8 ribonucleic acid compared with CD45+ blood progenitors or Dlk1+ 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.

Keywords

foetal liver - AGM - factor VIII - haemophilia therapy - newborn transplantation - LSEC

Authors' Contributions

Luis J. Serrano Ramos: collection and/or assembly of data, data analysis and interpretation. Ana Cañete: collection and/or assembly of data, data analysis and interpretation. Tamara Garcia-Leal: collection and/or assembly of data. Laura Tomas-Gallardo: collection and/or assembly of data. Ana I. Flores: revised critically the manuscript for important intellectual content. Paz de la Torre: revised critically the manuscript for important intellectual content. Antonio Liras: conception and design, financial support, revised critically the manuscript. Maria José Sanchez: conception and design, data analysis and interpretation, collection and assembly of data, financial support, manuscript writing. The final manuscript was read and approved by all authors.


* These authors have contributed equally as first authors.


** These authors have contributed equally as principal researchers to this work.


Supplementary Material

 

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