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Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis.

Stroo I, Stokman G, Teske GJ, Florquin S, Leemans JC - Nephrol. Dial. Transplant. (2009)

Bottom Line: Importantly, the amount of HSC in the ischemic kidney was markedly higher compared to the contralateral kidney.Neutralizing endogenous SDF-1 or HSC-associated CXCR4 did not prevent the migration of HSC.In conclusion, systemically administered HSC preferentially migrate to the ischemic injured kidney.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. I.Stroo@amc.uva.nl

ABSTRACT

Background: Haematopoietic stem cells (HSC) have been shown to migrate to the ischemic kidney. The factors that regulate the trafficking of HSC to the ischemic damaged kidney are not fully understood. The stromal cell-derived factor-1 (SDF-1)/CXCR4-axis has been identified as the central signalling axis regulating trafficking of HSC to the bone marrow. Therefore, we hypothesized that SDF-1/CXCR4 interactions are implicated in the migration of HSC to the injured kidney.

Methods: HSC were isolated from mouse bone marrow and labelled with a cell tracker. Acceptor mice were subjected to unilateral ischemia and received HSC intravenously directly after reperfusion. In addition, in separate groups of acceptor mice, endogenous SDF-1 or HSC-associated CXCR4 was blocked or kidneys were injected with SDF-1.

Results: Exogenous HSC could be detected in the tubules and interstitium of the kidney 24 h after ischemic injury. Importantly, the amount of HSC in the ischemic kidney was markedly higher compared to the contralateral kidney. Neutralizing endogenous SDF-1 or HSC-associated CXCR4 did not prevent the migration of HSC. No increase in the number of labelled HSC could be observed after local administration of SDF-1, as was also determined in bilateral kidney ischemia.

Conclusion: In conclusion, systemically administered HSC preferentially migrate to the ischemic injured kidney. This migration could not be prevented by blocking the SDF-1/CXCR4-axis or increased after local administration of SDF-1.

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Related in: MedlinePlus

HSC preferentially migrate to the ischemic injured kidney, and this migration is not altered by manipulating the SDF-1/CXCR4-axis. One day after unilateral ischemia for 55 min and subsequent intravenous administration of CM-DiI-labelled HSC, kidneys were harvested and analysed by flow cytometry for the presence of exogenous HSC (i.e. CM-DiI and c-Kit positive). Flow cytometry plots of (A) a contralateral and (B) an ischemic kidney demonstrate a higher percentage of exogenous HSC in the ischemic kidney. (C) Exogenous HSC in contralateral (□) and ischemic (▪) kidneys of mice with I/R injury and intravenously HSC (control) and of mice with additional neutralization of endogenous SDF-1 (anti-SDF-1), neutralization of HSC-associated CXCR4 (anti-CXCR4) and intrarenal recSDF-1 (recSDF-1), showed an increase in exogenous HSC in the ischemic kidney compared to the contralateral. However, this was only significant in the control and recSDF-1 mice (both *P = 0.03). Anti-SDF-1 or anti-CXCR4 treatment did not result in a decreased migration of HSC towards the ischemic kidney. Intrarenal recSDF-1 did not increase the migration of HSC towards the ischemic or contralateral kidney. Background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells. Data are expressed as mean ± SEM, n = 4.
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Figure 1: HSC preferentially migrate to the ischemic injured kidney, and this migration is not altered by manipulating the SDF-1/CXCR4-axis. One day after unilateral ischemia for 55 min and subsequent intravenous administration of CM-DiI-labelled HSC, kidneys were harvested and analysed by flow cytometry for the presence of exogenous HSC (i.e. CM-DiI and c-Kit positive). Flow cytometry plots of (A) a contralateral and (B) an ischemic kidney demonstrate a higher percentage of exogenous HSC in the ischemic kidney. (C) Exogenous HSC in contralateral (□) and ischemic (▪) kidneys of mice with I/R injury and intravenously HSC (control) and of mice with additional neutralization of endogenous SDF-1 (anti-SDF-1), neutralization of HSC-associated CXCR4 (anti-CXCR4) and intrarenal recSDF-1 (recSDF-1), showed an increase in exogenous HSC in the ischemic kidney compared to the contralateral. However, this was only significant in the control and recSDF-1 mice (both *P = 0.03). Anti-SDF-1 or anti-CXCR4 treatment did not result in a decreased migration of HSC towards the ischemic kidney. Intrarenal recSDF-1 did not increase the migration of HSC towards the ischemic or contralateral kidney. Background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells. Data are expressed as mean ± SEM, n = 4.

Mentions: To study the migration of HSC towards the injured kidney, mice were subjected to unilateral I/R injury, after which they received 0.6 × 106 CM-DiI-labelled HSC into the tail vein. Twenty-four hours later, there was a significant (P = 0.03) increase in HSC migrating to the ischemic injured kidney compared to the contralateral kidney as assessed by flow cytometric analysis (Figure 1). The background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells.


Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis.

Stroo I, Stokman G, Teske GJ, Florquin S, Leemans JC - Nephrol. Dial. Transplant. (2009)

HSC preferentially migrate to the ischemic injured kidney, and this migration is not altered by manipulating the SDF-1/CXCR4-axis. One day after unilateral ischemia for 55 min and subsequent intravenous administration of CM-DiI-labelled HSC, kidneys were harvested and analysed by flow cytometry for the presence of exogenous HSC (i.e. CM-DiI and c-Kit positive). Flow cytometry plots of (A) a contralateral and (B) an ischemic kidney demonstrate a higher percentage of exogenous HSC in the ischemic kidney. (C) Exogenous HSC in contralateral (□) and ischemic (▪) kidneys of mice with I/R injury and intravenously HSC (control) and of mice with additional neutralization of endogenous SDF-1 (anti-SDF-1), neutralization of HSC-associated CXCR4 (anti-CXCR4) and intrarenal recSDF-1 (recSDF-1), showed an increase in exogenous HSC in the ischemic kidney compared to the contralateral. However, this was only significant in the control and recSDF-1 mice (both *P = 0.03). Anti-SDF-1 or anti-CXCR4 treatment did not result in a decreased migration of HSC towards the ischemic kidney. Intrarenal recSDF-1 did not increase the migration of HSC towards the ischemic or contralateral kidney. Background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells. Data are expressed as mean ± SEM, n = 4.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698094&req=5

Figure 1: HSC preferentially migrate to the ischemic injured kidney, and this migration is not altered by manipulating the SDF-1/CXCR4-axis. One day after unilateral ischemia for 55 min and subsequent intravenous administration of CM-DiI-labelled HSC, kidneys were harvested and analysed by flow cytometry for the presence of exogenous HSC (i.e. CM-DiI and c-Kit positive). Flow cytometry plots of (A) a contralateral and (B) an ischemic kidney demonstrate a higher percentage of exogenous HSC in the ischemic kidney. (C) Exogenous HSC in contralateral (□) and ischemic (▪) kidneys of mice with I/R injury and intravenously HSC (control) and of mice with additional neutralization of endogenous SDF-1 (anti-SDF-1), neutralization of HSC-associated CXCR4 (anti-CXCR4) and intrarenal recSDF-1 (recSDF-1), showed an increase in exogenous HSC in the ischemic kidney compared to the contralateral. However, this was only significant in the control and recSDF-1 mice (both *P = 0.03). Anti-SDF-1 or anti-CXCR4 treatment did not result in a decreased migration of HSC towards the ischemic kidney. Intrarenal recSDF-1 did not increase the migration of HSC towards the ischemic or contralateral kidney. Background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells. Data are expressed as mean ± SEM, n = 4.
Mentions: To study the migration of HSC towards the injured kidney, mice were subjected to unilateral I/R injury, after which they received 0.6 × 106 CM-DiI-labelled HSC into the tail vein. Twenty-four hours later, there was a significant (P = 0.03) increase in HSC migrating to the ischemic injured kidney compared to the contralateral kidney as assessed by flow cytometric analysis (Figure 1). The background fluorescence of ischemic and contralateral kidneys without HSC administration was subtracted to correct for autofluorescence of (dead) cells.

Bottom Line: Importantly, the amount of HSC in the ischemic kidney was markedly higher compared to the contralateral kidney.Neutralizing endogenous SDF-1 or HSC-associated CXCR4 did not prevent the migration of HSC.In conclusion, systemically administered HSC preferentially migrate to the ischemic injured kidney.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. I.Stroo@amc.uva.nl

ABSTRACT

Background: Haematopoietic stem cells (HSC) have been shown to migrate to the ischemic kidney. The factors that regulate the trafficking of HSC to the ischemic damaged kidney are not fully understood. The stromal cell-derived factor-1 (SDF-1)/CXCR4-axis has been identified as the central signalling axis regulating trafficking of HSC to the bone marrow. Therefore, we hypothesized that SDF-1/CXCR4 interactions are implicated in the migration of HSC to the injured kidney.

Methods: HSC were isolated from mouse bone marrow and labelled with a cell tracker. Acceptor mice were subjected to unilateral ischemia and received HSC intravenously directly after reperfusion. In addition, in separate groups of acceptor mice, endogenous SDF-1 or HSC-associated CXCR4 was blocked or kidneys were injected with SDF-1.

Results: Exogenous HSC could be detected in the tubules and interstitium of the kidney 24 h after ischemic injury. Importantly, the amount of HSC in the ischemic kidney was markedly higher compared to the contralateral kidney. Neutralizing endogenous SDF-1 or HSC-associated CXCR4 did not prevent the migration of HSC. No increase in the number of labelled HSC could be observed after local administration of SDF-1, as was also determined in bilateral kidney ischemia.

Conclusion: In conclusion, systemically administered HSC preferentially migrate to the ischemic injured kidney. This migration could not be prevented by blocking the SDF-1/CXCR4-axis or increased after local administration of SDF-1.

Show MeSH
Related in: MedlinePlus