Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing

Abstract

Hematopoietic cells have been reported to convert into a number of non-hematopoietic cells types after transplantation/injury. Here, we have used a lineage tracing approach to determine whether hematopoietic plasticity is relevant for the normal development of hepatocytes and endothelial cells, both of which develop in close association with blood cells. Two mouse models were analyzed: vav ancestry mice, in which essentially all hematopoietic cells,including stem cells, irreversibly express yellow fluorescent protein (YFP);and lysozyme ancestry mice, in which all macrophages, as well as a small subset of all other non-myeloid hematopoietic cells, are labeled. Both lines were found to contain YFP+ hepatocytes at similar frequencies,indicating that macrophage to hepatocyte contributions occur in unperturbed mice. However, the YFP+ hepatocytes never formed clusters larger than three cells, suggesting a postnatal origin. In addition, the frequency of these cells was very low (∼1 in 75,000) and only increased two- to threefold after acute liver injury. Analysis of the two mouse models revealed no evidence for a hematopoietic origin of endothelial cells, showing that definitive HSCs do not function as hemangioblasts during normal development. Using endothelial cells and hepatocytes as paradigms, our study indicates that hematopoietic cells are tightly restricted in their differentiation potential during mouse embryo development and that hematopoietic plasticity plays at best a minor role in adult organ maintenance and regeneration.

Dendritic cell fate is determined by BCL11A

“…The floxed (F) allele of Bcl11a was crossed to transgenic mice in which Cre recombinase is driven by the promoter of the Vav gene (38). The iVav-cre transgene is expressed in HSCs and in all downstream lineages (39), allowing reliable deletion throughout the entire embryonic and adult hematopoietic compartment.…”

Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

“…The Vav-Cre transgene provides efficient excision during an early stage of haematopoietic development when many cell lineage precursors are actively proliferating. 7,41 Haematopoietic excision of Erk5 resulted in enlarged spleen and increased spleen cellularity in mice aged 1-2 months old, whereas bone marrow cellularity was unaltered (Fig. 5B, C, D, E).…”

“…7 Erk5 fl/fl mice were bred to Vav-Cre mice kindly provided by Thomas Graf (CRG, Universitat Pompeu Fabra, Barcelona, Spain). 41 All mice were treated in accordance with institutional guidelines and national laws and policies, and procedures were approved by the Departament d' Agricultura, Ramaderia, Pesca, Alimentacio i Medi Natural of Generalitat de Catalunya. Experiments were conducted on 4 and 8 week-old mice.…”

The methyltransferase G9a regulates HoxA9-dependent transcription in AML

“…1A; Lehnertz et al 2010) crossed with Vav-Cre transgenic mice to obtain G9a +/fl ; Vav-Cre and G9a fl/fl ; Vav-Cre mice [G9a +/À (Vav) and G9a À/À (Vav) , hereafter]. As expected (Stadtfeld and Graf 2005;Gan et al 2010), Vav-Cre-mediated excision in G9a À/À (Vav) mice harboring a ROSA26-YFP (R26-YFP) Cre reporter was specific to hematopoietic cells and fully penetrant . Consistent with previous reports (Tachibana et al 2002(Tachibana et al , 2005, deletion of G9a resulted in a characteristic reduction in GLP and H3K9me2 levels in bone marrow-derived macrophages (BMMs) (Fig.…”

“…G9a fl mice (Lehnertz et al 2010), Vav-Cre mice (Stadtfeld and Graf 2005), and R26-YFP mice (Ye et al 2003) were described earlier, and Mx-Cre mice were obtained from Jackson Laboratory. …”