Characterization of a Fetal Liver Cell Population Endowed with Long‐Term Multiorgan Endothelial Reconstitution Potential. (28th September 2016)

• Record Type: Journal Article
• Authors: Cañete, Ana; Comaills, Valentine; Prados, Isabel; Castro, Ana María; Hammad, Seddik; Ybot‐Gonzalez, Patricia; Bockamp, Ernesto; Hengstler, Jan G.; Gottgens, Bertie; Sánchez, María José
• Is Part Of: Stem cells. Volume 35:Number 2(2017:Feb.)
• Page Start: 507
• Page End: 521
• Publication Date: 2016-09-28
• Subjects: Progenitor cells -- Hematopoietic progenitors -- Fetal liver -- Endothelial reconstitution -- Newborn transplantation; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2494
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: 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 Abstract : (A) : SCL‐PLAP + VE‐cad + CD45 −, Lyve1 +/‐ (P + V + C − ) fetal liver derived cells generate long term vascular endothelial clusters in different organs when intravenously transplanted into busulfan conditioned newborn recipient mice. P + V + C − cells contributed to endothelial cells (arrows) and also to rare blood cells (asterisks). Scale bars 50 μm.(B) : As early as 3 weeks post‐transplantation, transferred fetal liver progenitor cells already form PLAP + vascular clusters (vc) in the host liver. The functionality of the vascular grafts is indicated by the presence of circulating cells in the vessels lumen (i, asterisk), implying their participation in the systemic circulation. Also the higher frequency of BrdU + hepatocytes‐like cells detected in expanding vascular cluster (in vc) areas (ii ) compared with tissue areas outside the vascular clusters (out vc) (iv ), suggests that donor‐host cellularity cross‐talk activity involved in proliferation control occurs during organ growth. At later stages (12 weeks), when the organ growth slows down and vascular graft expansion stabilizes, almost no BrdU + cells are observed within the vascular cluster areas (iii andiv ) indicating the absence of continuing proliferation in the grafted region. Scale bars 60 μm.