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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)644-653
Number of pages10
JournalDiabetologia
Volume56
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

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Hematopoietic Stem Cells
Type 1 Diabetes Mellitus
Blood Vessels
Monocytes
Bone Marrow
Bone Marrow Cells
Retina
Cell Count
Side-Population Cells
Cytokines
Population
Kidney
Protein Array Analysis
Hematopoiesis
Streptozocin
Glycoproteins
Flow Cytometry
Nitric Oxide
Oxidative Stress
Enzyme-Linked Immunosorbent Assay

Keywords

  • Bone marrow microenvironment
  • Endothelial progenitors
  • GP130 deletion
  • Haematopoietic stem cells
  • IL-1β and IL-10
  • MMPs
  • Monocytes
  • Side population cells
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. / Hazra, S.; Jarajapu, Y. P R; Stepps, V.; Caballero, S.; Thinschmidt, J. S.; Sautina, L.; Bengtsson, N.; Licalzi, S.; Dominguez, J.; Kern, T. S.; Segal, M. S.; Ash, J. D.; Saban, D. R.; Bartelmez, S. H.; Grant, M. B.

In: Diabetologia, Vol. 56, No. 3, 03.2013, p. 644-653.

Research output: Contribution to journalArticle

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 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, vol. 56, no. 3, pp. 644-653. https://doi.org/10.1007/s00125-012-2781-0
Hazra, S. ; Jarajapu, Y. P R ; Stepps, V. ; Caballero, S. ; Thinschmidt, J. S. ; Sautina, L. ; Bengtsson, N. ; Licalzi, S. ; Dominguez, J. ; Kern, T. S. ; Segal, M. S. ; Ash, J. D. ; Saban, D. R. ; Bartelmez, S. H. ; Grant, M. B. / Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. In: Diabetologia. 2013 ; Vol. 56, No. 3. pp. 644-653.
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T1 - Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model

AU - Hazra, S.

AU - Jarajapu, Y. P R

AU - Stepps, V.

AU - Caballero, S.

AU - Thinschmidt, J. S.

AU - Sautina, L.

AU - Bengtsson, N.

AU - Licalzi, S.

AU - Dominguez, J.

AU - Kern, T. S.

AU - Segal, M. S.

AU - Ash, J. D.

AU - Saban, D. R.

AU - Bartelmez, S. H.

AU - Grant, M. B.

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

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KW - Endothelial progenitors

KW - GP130 deletion

KW - Haematopoietic stem cells

KW - IL-1β and IL-10

KW - MMPs

KW - Monocytes

KW - Side population cells

KW - Type 1 diabetes

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