TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization

Akm Khyrul Wara, Shi Yin Foo, Kevin Croce, Xinghui Sun, Basak Icli, Yevgenia Tesmenitsky, Fehim Esen, Jung Soo Lee, Malayannan Subramaniam, Thomas C. Spelsberg, Eli I. Lev, Dorit Leshem-Lev, Reena L. Pande, Mark A. Creager, Anthony Rosenzweig, Mark W. Feinberg

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Krüppel-like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼60-fold higher than in progenitors lacking PAC markers. KLF10 -/- mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10 -/- PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1 -/- CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.

Original languageEnglish (US)
Pages (from-to)6450-6460
Number of pages11
JournalBlood
Volume118
Issue number24
DOIs
StatePublished - Dec 8 2011

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Macrophages
Stem cells
Cell Differentiation
Bone
Blood
Bone Marrow
Recovery
Defects
Myeloid Progenitor Cells
Hematopoietic Stem Cells
Granulocyte-Macrophage Progenitor Cells
Peripheral Arterial Disease
Hindlimb
Ischemia

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization. / Wara, Akm Khyrul; Foo, Shi Yin; Croce, Kevin; Sun, Xinghui; Icli, Basak; Tesmenitsky, Yevgenia; Esen, Fehim; Lee, Jung Soo; Subramaniam, Malayannan; Spelsberg, Thomas C.; Lev, Eli I.; Leshem-Lev, Dorit; Pande, Reena L.; Creager, Mark A.; Rosenzweig, Anthony; Feinberg, Mark W.

In: Blood, Vol. 118, No. 24, 08.12.2011, p. 6450-6460.

Research output: Contribution to journalArticle

Wara, AK, Foo, SY, Croce, K, Sun, X, Icli, B, Tesmenitsky, Y, Esen, F, Lee, JS, Subramaniam, M, Spelsberg, TC, Lev, EI, Leshem-Lev, D, Pande, RL, Creager, MA, Rosenzweig, A & Feinberg, MW 2011, 'TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization', Blood, vol. 118, no. 24, pp. 6450-6460. https://doi.org/10.1182/blood-2011-06-363713
Wara, Akm Khyrul ; Foo, Shi Yin ; Croce, Kevin ; Sun, Xinghui ; Icli, Basak ; Tesmenitsky, Yevgenia ; Esen, Fehim ; Lee, Jung Soo ; Subramaniam, Malayannan ; Spelsberg, Thomas C. ; Lev, Eli I. ; Leshem-Lev, Dorit ; Pande, Reena L. ; Creager, Mark A. ; Rosenzweig, Anthony ; Feinberg, Mark W. / TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization. In: Blood. 2011 ; Vol. 118, No. 24. pp. 6450-6460.
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abstract = "Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Kr{\"u}ppel-like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼60-fold higher than in progenitors lacking PAC markers. KLF10 -/- mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10 -/- PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1 -/- CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.",
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T1 - TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization

AU - Wara, Akm Khyrul

AU - Foo, Shi Yin

AU - Croce, Kevin

AU - Sun, Xinghui

AU - Icli, Basak

AU - Tesmenitsky, Yevgenia

AU - Esen, Fehim

AU - Lee, Jung Soo

AU - Subramaniam, Malayannan

AU - Spelsberg, Thomas C.

AU - Lev, Eli I.

AU - Leshem-Lev, Dorit

AU - Pande, Reena L.

AU - Creager, Mark A.

AU - Rosenzweig, Anthony

AU - Feinberg, Mark W.

PY - 2011/12/8

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N2 - Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Krüppel-like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼60-fold higher than in progenitors lacking PAC markers. KLF10 -/- mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10 -/- PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1 -/- CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.

AB - Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-β1-responsive Krüppel-like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ∼60-fold higher than in progenitors lacking PAC markers. KLF10 -/- mice present with marked defects in PAC differentiation, function, TGF-β responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10 -/- PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF-β1 -/- CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-β1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states.

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