Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1α mediated bone marrow mobilization impair diabetic tissue repair

Oren M. Tepper, Jacquelyn Carr, Robert J. Allen, Christopher C. Chang, Clarence D. Lin, Rica Tanaka, Sanjeev M. Gupta, Jamie P. Levine, Pierre B. Saadeh, Stephen M. Warren

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

OBJECTIVE - Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing. RESEARCH DESIGN AND METHODS - Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points. RESULTS - Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin -/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2% lin-/ckit+/sca1+ vs. 13.5 ± 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin-/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0% vs. 11.9 ± 3% at day 7, P > 0.05; 73.0 ± 6.4% vs. 36.5 ± 7% at day 14, P < 0.05; and 88.0 ± 5.7% vs. 66.7 ± 5% at day 21, P > 0.05, respectively). CONCLUSIONS - Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemiamediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.

Original languageEnglish (US)
Pages (from-to)1974-1983
Number of pages10
JournalDiabetes
Volume59
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

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Chemokine CXCL12
Stem Cells
Cell Count
Bone Marrow
Bone Marrow Cells
Wounds and Injuries
Research Design
Ischemia
Pathology
Skin

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1α mediated bone marrow mobilization impair diabetic tissue repair. / Tepper, Oren M.; Carr, Jacquelyn; Allen, Robert J.; Chang, Christopher C.; Lin, Clarence D.; Tanaka, Rica; Gupta, Sanjeev M.; Levine, Jamie P.; Saadeh, Pierre B.; Warren, Stephen M.

In: Diabetes, Vol. 59, No. 8, 08.2010, p. 1974-1983.

Research output: Contribution to journalArticle

Tepper, Oren M. ; Carr, Jacquelyn ; Allen, Robert J. ; Chang, Christopher C. ; Lin, Clarence D. ; Tanaka, Rica ; Gupta, Sanjeev M. ; Levine, Jamie P. ; Saadeh, Pierre B. ; Warren, Stephen M. / Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1α mediated bone marrow mobilization impair diabetic tissue repair. In: Diabetes. 2010 ; Vol. 59, No. 8. pp. 1974-1983.
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title = "Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1α mediated bone marrow mobilization impair diabetic tissue repair",
abstract = "OBJECTIVE - Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing. RESEARCH DESIGN AND METHODS - Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points. RESULTS - Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin -/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2{\%} lin-/ckit+/sca1+ vs. 13.5 ± 2.8{\%} in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40{\%} reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8{\%} reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54{\%} reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin-/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0{\%} vs. 11.9 ± 3{\%} at day 7, P > 0.05; 73.0 ± 6.4{\%} vs. 36.5 ± 7{\%} at day 14, P < 0.05; and 88.0 ± 5.7{\%} vs. 66.7 ± 5{\%} at day 21, P > 0.05, respectively). CONCLUSIONS - Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemiamediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.",
author = "Tepper, {Oren M.} and Jacquelyn Carr and Allen, {Robert J.} and Chang, {Christopher C.} and Lin, {Clarence D.} and Rica Tanaka and Gupta, {Sanjeev M.} and Levine, {Jamie P.} and Saadeh, {Pierre B.} and Warren, {Stephen M.}",
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T1 - Decreased circulating progenitor cell number and failed mechanisms of stromal cell-derived factor-1α mediated bone marrow mobilization impair diabetic tissue repair

AU - Tepper, Oren M.

AU - Carr, Jacquelyn

AU - Allen, Robert J.

AU - Chang, Christopher C.

AU - Lin, Clarence D.

AU - Tanaka, Rica

AU - Gupta, Sanjeev M.

AU - Levine, Jamie P.

AU - Saadeh, Pierre B.

AU - Warren, Stephen M.

PY - 2010/8

Y1 - 2010/8

N2 - OBJECTIVE - Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing. RESEARCH DESIGN AND METHODS - Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points. RESULTS - Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin -/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2% lin-/ckit+/sca1+ vs. 13.5 ± 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin-/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0% vs. 11.9 ± 3% at day 7, P > 0.05; 73.0 ± 6.4% vs. 36.5 ± 7% at day 14, P < 0.05; and 88.0 ± 5.7% vs. 66.7 ± 5% at day 21, P > 0.05, respectively). CONCLUSIONS - Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemiamediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.

AB - OBJECTIVE - Progenitor cells (PCs) contribute to postnatal neovascularization and tissue repair. Here, we explore the mechanism contributing to decreased diabetic circulating PC number and propose a novel treatment to restore circulating PC number, peripheral neovascularization, and tissue healing. RESEARCH DESIGN AND METHODS - Cutaneous wounds were created on wild-type (C57BL/J6) and diabetic (Leprdb/db) mice. Blood and bone marrow PCs were collected at multiple time points. RESULTS - Significantly delayed wound closure in diabetic animals was associated with diminished circulating PC number (1.9-fold increase vs. 7.6-fold increase in lin -/sca-1+/ckit+ in wild-type mice; P < 0.01), despite adequate numbers of PCs in the bone marrow at baseline (14.4 ± 3.2% lin-/ckit+/sca1+ vs. 13.5 ± 2.8% in wild-type). Normal bone marrow PC mobilization in response to peripheral wounding occurred after a necessary switch in bone marrow stromal cell-derived factor-1α (SDF-1α) expression (40% reduction, P < 0.01). In contrast, a failed switch mechanism in diabetic bone marrow SDF-1α expression (2.8% reduction) resulted in impaired PC mobilization. Restoring the bone marrow SDF-1α switch (54% reduction, P < 0.01) with plerixafor (Mozobil, formerly known as AMD3100) increased circulating diabetic PC numbers (6.8 ± 2.0-fold increase in lin-/ckit+, P < 0.05) and significantly improved diabetic wound closure compared with sham-treated controls (32.9 ± 5.0% vs. 11.9 ± 3% at day 7, P > 0.05; 73.0 ± 6.4% vs. 36.5 ± 7% at day 14, P < 0.05; and 88.0 ± 5.7% vs. 66.7 ± 5% at day 21, P > 0.05, respectively). CONCLUSIONS - Successful ischemia-induced bone marrow PC mobilization is mediated by a switch in bone marrow SDF-1α levels. In diabetes, this switch fails to occur. Plerixafor represents a potential therapeutic agent for improving ischemiamediated pathology associated with diabetes by reducing bone marrow SDF-1α, restoring normal PC mobilization and tissue healing.

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