CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity

Min Cheng, Junlan Zhou, Min Wu, Chan Boriboun, Tina Thorne, Ting Liu, Zhifu Xiang, Qiutang Zeng, Toshikazu Tanaka, Yao Liang Tang, Raj Kishore, Michael H. Tomasson, Richard J. Miller, Douglas W. Losordo, Gangjian Qin

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair. Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Methods and Results: AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF-1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src. Conclusions: These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation.

Original languageEnglish (US)
Pages (from-to)1083-1093
Number of pages11
JournalCirculation research
Volume107
Issue number9
DOIs
StatePublished - Oct 29 2010
Externally publishedYes

Fingerprint

Chemokine CXCL12
Bone Marrow Cells
Stem Cells
Maintenance
Phosphorylation
Stem Cell Factor
CXCR4 Receptors
src-Family Kinases
Vascular Cell Adhesion Molecule-1
Receptor Protein-Tyrosine Kinases
Phosphotransferases
Bone Marrow
Pharmacology
Membranes
JM 3100
Wounds and Injuries

Keywords

  • CXCR4
  • bone marrow
  • c-kit
  • mobilization
  • stem cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity. / Cheng, Min; Zhou, Junlan; Wu, Min; Boriboun, Chan; Thorne, Tina; Liu, Ting; Xiang, Zhifu; Zeng, Qiutang; Tanaka, Toshikazu; Tang, Yao Liang; Kishore, Raj; Tomasson, Michael H.; Miller, Richard J.; Losordo, Douglas W.; Qin, Gangjian.

In: Circulation research, Vol. 107, No. 9, 29.10.2010, p. 1083-1093.

Research output: Contribution to journalArticle

Cheng, M, Zhou, J, Wu, M, Boriboun, C, Thorne, T, Liu, T, Xiang, Z, Zeng, Q, Tanaka, T, Tang, YL, Kishore, R, Tomasson, MH, Miller, RJ, Losordo, DW & Qin, G 2010, 'CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity', Circulation research, vol. 107, no. 9, pp. 1083-1093. https://doi.org/10.1161/CIRCRESAHA.110.220970
Cheng, Min ; Zhou, Junlan ; Wu, Min ; Boriboun, Chan ; Thorne, Tina ; Liu, Ting ; Xiang, Zhifu ; Zeng, Qiutang ; Tanaka, Toshikazu ; Tang, Yao Liang ; Kishore, Raj ; Tomasson, Michael H. ; Miller, Richard J. ; Losordo, Douglas W. ; Qin, Gangjian. / CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity. In: Circulation research. 2010 ; Vol. 107, No. 9. pp. 1083-1093.
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abstract = "Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair. Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Methods and Results: AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF-1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src. Conclusions: These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation.",
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T1 - CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity

AU - Cheng, Min

AU - Zhou, Junlan

AU - Wu, Min

AU - Boriboun, Chan

AU - Thorne, Tina

AU - Liu, Ting

AU - Xiang, Zhifu

AU - Zeng, Qiutang

AU - Tanaka, Toshikazu

AU - Tang, Yao Liang

AU - Kishore, Raj

AU - Tomasson, Michael H.

AU - Miller, Richard J.

AU - Losordo, Douglas W.

AU - Qin, Gangjian

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N2 - Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair. Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Methods and Results: AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF-1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src. Conclusions: These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation.

AB - Rationale: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair. Objective: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. Methods and Results: AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF-1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src. Conclusions: These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation.

KW - CXCR4

KW - bone marrow

KW - c-kit

KW - mobilization

KW - stem cells

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