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Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

Flaquer M, Franquesa M, Vidal A, Bolaños N, Torras J, Lloberas N, Herrero-Fresneda I, Grinyó JM, Cruzado JM - Diabetologia (2012)

Bottom Line: The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells.These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Laboratory, Departament de Ciències Clíniques, IDIBELL, University of Barcelona, Bellvitge Hospital, Barcelona, Spain.

ABSTRACT

Aims/hypothesis: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.

Methods: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals.

Results: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation.

Conclusions/interpretation: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

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Renal EGFP+ cells are mainly macrophages. The arrows show macrophages stained with F4/80 (in red), which co-express EGFP (in green) becoming yellow and therefore suggesting a bone marrow origin. Arrowheads show EGFP+ cells (in green). Asterisks show some macrophages stained with F4/80 (in red) that do not co-express EGFP (×630)
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Fig6: Renal EGFP+ cells are mainly macrophages. The arrows show macrophages stained with F4/80 (in red), which co-express EGFP (in green) becoming yellow and therefore suggesting a bone marrow origin. Arrowheads show EGFP+ cells (in green). Asterisks show some macrophages stained with F4/80 (in red) that do not co-express EGFP (×630)

Mentions: There were very few mesenchymal stem cells and all of them were EGFP− (data not shown). Nevertheless, the majority of EGFP+ cells located in the kidney expressed the macrophage marker F4/80 (Fig. 6). However, there were also a small number of EGFP− macrophages. Macrophages were mainly localised around the glomeruli and in the interstitial area. Nearly all of the F4/80+ cells were EPGP+, which means these cells were bone-marrow-derived macrophages.Fig. 6


Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

Flaquer M, Franquesa M, Vidal A, Bolaños N, Torras J, Lloberas N, Herrero-Fresneda I, Grinyó JM, Cruzado JM - Diabetologia (2012)

Renal EGFP+ cells are mainly macrophages. The arrows show macrophages stained with F4/80 (in red), which co-express EGFP (in green) becoming yellow and therefore suggesting a bone marrow origin. Arrowheads show EGFP+ cells (in green). Asterisks show some macrophages stained with F4/80 (in red) that do not co-express EGFP (×630)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369134&req=5

Fig6: Renal EGFP+ cells are mainly macrophages. The arrows show macrophages stained with F4/80 (in red), which co-express EGFP (in green) becoming yellow and therefore suggesting a bone marrow origin. Arrowheads show EGFP+ cells (in green). Asterisks show some macrophages stained with F4/80 (in red) that do not co-express EGFP (×630)
Mentions: There were very few mesenchymal stem cells and all of them were EGFP− (data not shown). Nevertheless, the majority of EGFP+ cells located in the kidney expressed the macrophage marker F4/80 (Fig. 6). However, there were also a small number of EGFP− macrophages. Macrophages were mainly localised around the glomeruli and in the interstitial area. Nearly all of the F4/80+ cells were EPGP+, which means these cells were bone-marrow-derived macrophages.Fig. 6

Bottom Line: The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells.These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Laboratory, Departament de Ciències Clíniques, IDIBELL, University of Barcelona, Bellvitge Hospital, Barcelona, Spain.

ABSTRACT

Aims/hypothesis: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process.

Methods: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals.

Results: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation.

Conclusions/interpretation: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.

Show MeSH
Related in: MedlinePlus