Characterization of a Fetal Liver Cell Population Endowed with Long-Term Multiorgan Endothelial Reconstitution Potential.
Stable reconstitution of vascular endothelial beds upon transplantation of progenitor cells represents an important challenge due to the paucity and generally limited integration/expansion potential of most identified vascular related cell subsets. We previously showed that mouse fetal liver (FL) hemato/vascular cells from day 12 of gestation (E12), expressing the Stem Cell Leukaemia (SCL) gene enhancer transgene (SCL-PLAP+cells), had robust endothelial engraftment potential when transferred to the blood stream of newborns or adult conditioned recipients, compared to the scarce vascular contribution of adult bone marrow cells. However, the specific SCL-PLAP+hematopoietic or endothelial cell subset responsible for the long-term reconstituting endothelial cell (LTR-EC) activity and its confinement to FL developmental stages remained unknown. Using a busulfan-treated newborn transplantation model, we show that LTR-EC activity is restricted to the SCL-PLAP+VE-cadherin+CD45-cell population, devoid of hematopoietic reconstitution activity and largely composed by Lyve1+endothelial-committed cells. SCL-PLAP+Ve-cadherin+CD45-cells contributed to the liver sinusoidal endothelium and also to the heart, kidney and lung microvasculature. LTR-EC activity was detected at different stages of FL development, yet marginal activity was identified in the adult liver, revealing unknown functional differences between fetal and adult liver endothelial/endothelial progenitors. Importantly, the observations that expanding donor-derived vascular grafts colocalize with proliferating hepatocyte-like cells and participate in the systemic circulation, support their functional integration into young livers. These findings offer new insights into the engraftment, phonotypical, and developmental characterization of a novel endothelial/endothelial progenitor cell subtype with multiorgan LTR-EC activity, potentially instrumental for the treatment/genetic correction of vascular diseases. Stem Cells 2017;35:507-521.
Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía (JA), Universidad Pablo de Olavide (UPO), Sevilla, Spain.
Ana
A
Cañete
Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía (JA), Universidad Pablo de Olavide (UPO), Sevilla, Spain.
Valentine
V
Comaills
Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía (JA), Universidad Pablo de Olavide (UPO), Sevilla, Spain.
Isabel
I
Prados
Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía (JA), Universidad Pablo de Olavide (UPO), Sevilla, Spain.
Ana María
AM
Castro
Faculty of Veterinary Medicine, Department of Forensic Medicine and Veterinary Toxicology, South Valley University, Qena, Egypt.|Leibniz Research Center for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
Seddik
S
Hammad
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.
Patricia
P
Ybot-Gonzalez
Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Ernesto
E
Bockamp
Leibniz Research Center for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
Jan G
JG
Hengstler
Cambridge Institute for Medical Research & Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge University, United Kingdom.
Bertie
B
Gottgens
Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía (JA), Universidad Pablo de Olavide (UPO), Sevilla, Spain.
María José
MJ
Sánchez
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001808:Blood Vessels / Q000637:transplantation; D015820:Cadherins / Q000378:metabolism; D002449:Cell Aggregation; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005333:Fetus / Q000166:cytology* / Q000196:embryology*; D006410:Hematopoiesis; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008099:Liver / Q000196:embryology*; D051379:Mice; D009928:Organ Specificity; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1 / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D017493:Leukocyte Common Antigens; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D000099152:Cadherin 5; C511592:Aspn protein, mouse
Endothelial reconstitution; Fetal liver; Hematopoietic progenitors; Newborn transplantation; Progenitor cells