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Diabetologia
Published in: Diabetologia 3/2013

01-03-2013 | Article

Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model

Authors: S. Hazra, Y. P. R. Jarajapu, V. Stepps, S. Caballero, J. S. Thinschmidt, L. Sautina, N. Bengtsson, S. LiCalzi, J. Dominguez, T. S. Kern, M. S. Segal, J. D. Ash, D. R. Saban, S. H. Bartelmez, M. B. Grant

Published in: Diabetologia | Issue 3/2013

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Abstract

Aims/hypothesis

We sought to determine the impact of long-standing type 1 diabetes on haematopoietic stem/progenitor cell (HSC) number and function and to examine the impact of modulating glycoprotein (GP)130 receptor in these cells.

Methods

Wild-type, gp130 −/− and GFP chimeric mice were treated with streptozotocin to induce type 1 diabetes. Bone marrow (BM)-derived cells were used for colony-formation assay, quantification of side population (SP) cells, examination of gene expression, nitric oxide measurement and migration studies. Endothelial progenitor cells (EPCs), a population of vascular precursors derived from HSCs, were compared in diabetic and control mice. Cytokines were measured in BM supernatant fractions by ELISA and protein array. Flow cytometry was performed on enzymatically dissociated retina from gfp + chimeric mice and used to assess BM cell recruitment to the retina, kidney and blood.

Results

BM cells from the 12-month-diabetic mice showed reduced colony-forming ability, depletion of SP-HSCs with a proportional increase in SP-HSCs residing in hypoxic regions of BM, decreased EPC numbers, and reduced eNos (also known as Nos3) but increased iNos (also known as Nos2) and oxidative stress-related genes. BM supernatant fraction showed increased cytokines, GP130 ligands and monocyte/macrophage stimulating factor. Retina, kidney and peripheral blood showed increased numbers of CD11b+/CD45hi/ CCR2+/Ly6Chi inflammatory monocytes. Diabetic gp130 −/− mice were protected from development of diabetes-induced changes in their HSCs.

Conclusions/interpretation

The BM microenvironment of type 1 diabetic mice can lead to changes in haematopoiesis, with generation of more monocytes and fewer EPCs contributing to development of microvascular complications. Inhibition of GP130 activation may serve as a therapeutic strategy to improve the key aspects of this dysfunction.
Appendix
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Metadata
Title
Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model
Authors
S. Hazra
Y. P. R. Jarajapu
V. Stepps
S. Caballero
J. S. Thinschmidt
L. Sautina
N. Bengtsson
S. LiCalzi
J. Dominguez
T. S. Kern
M. S. Segal
J. D. Ash
D. R. Saban
S. H. Bartelmez
M. B. Grant
Publication date
01-03-2013
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2781-0

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