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

Publication ,  Journal Article
Hazra, S; Jarajapu, YPR; Stepps, V; Caballero, S; Thinschmidt, JS; Sautina, L; Bengtsson, N; Licalzi, S; Dominguez, J; Kern, TS; Segal, MS ...
Published in: Diabetologia
March 2013

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(+)/CD45(hi)/ CCR2(+)/Ly6C(hi) 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.

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Published In

Diabetologia

DOI

EISSN

1432-0428

Publication Date

March 2013

Volume

56

Issue

3

Start / End Page

644 / 653

Location

Germany

Related Subject Headings

  • Monocytes
  • Mice, Mutant Strains
  • Mice, Knockout
  • Mice
  • Interleukin-1beta
  • Interleukin-10
  • Hematopoietic Stem Cells
  • Endothelial Cells
  • Endocrinology & Metabolism
  • Diabetes Mellitus, Type 1
 

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Hazra, S., Jarajapu, Y. P. R., Stepps, V., Caballero, S., Thinschmidt, J. S., Sautina, L., … Grant, M. B. (2013). Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia, 56(3), 644–653. https://doi.org/10.1007/s00125-012-2781-0
Hazra, S., Y. P. R. Jarajapu, V. Stepps, S. Caballero, J. S. Thinschmidt, L. Sautina, N. Bengtsson, et al. “Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model.Diabetologia 56, no. 3 (March 2013): 644–53. https://doi.org/10.1007/s00125-012-2781-0.
Hazra S, Jarajapu YPR, Stepps V, Caballero S, Thinschmidt JS, Sautina L, et al. Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia. 2013 Mar;56(3):644–53.
Hazra, S., et al. “Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model.Diabetologia, vol. 56, no. 3, Mar. 2013, pp. 644–53. Pubmed, doi:10.1007/s00125-012-2781-0.
Hazra S, Jarajapu YPR, Stepps V, Caballero S, Thinschmidt JS, Sautina L, Bengtsson N, Licalzi S, Dominguez J, Kern TS, Segal MS, Ash JD, Saban DR, Bartelmez SH, Grant MB. Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia. 2013 Mar;56(3):644–653.
Journal cover image

Published In

Diabetologia

DOI

EISSN

1432-0428

Publication Date

March 2013

Volume

56

Issue

3

Start / End Page

644 / 653

Location

Germany

Related Subject Headings

  • Monocytes
  • Mice, Mutant Strains
  • Mice, Knockout
  • Mice
  • Interleukin-1beta
  • Interleukin-10
  • Hematopoietic Stem Cells
  • Endothelial Cells
  • Endocrinology & Metabolism
  • Diabetes Mellitus, Type 1