Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling

Michelle I. Lin; Emily N. Price; Sonja Boatman; Elliott J. Hagedorn; Eirini Trompouki; Sruthi Satishchandran; Charles W. Carspecken; Audrey Uong; Anthony DiBiase; Song Yang; Matthew C. Canver; Ann Dahlberg; Zhigang Lu; Chengcheng Zhang; Stuart H. Orkin; Irwin D. Bernstein; Jon C. Aster; Richard M. White; Leonard I. Zon

doi:10.7554/eLife.05544

Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling

Michelle I. Lin, Emily N. Price, Sonja Boatman, Elliott J. Hagedorn, Eirini Trompouki, Sruthi Satishchandran, Charles W. Carspecken, Audrey Uong, Anthony DiBiase, Song Yang, Matthew C. Canver, Ann Dahlberg, Zhigang Lu, Chengcheng Zhang, Stuart H. Orkin, Irwin D. Bernstein, Jon C. Aster, Richard M. White, Leonard I. Zon

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. Here, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib) and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in Angptl2-stimulated CD34⁺ cells showed a strong Myc activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. Angptl2 can increase Notch activation in cultured cells and Angptl receptor interacted with Notch to regulate Notch cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets.

Original language	English (US)
Article number	e05544
Journal	eLife
Volume	2015
Issue number	4
DOIs	https://doi.org/10.7554/eLife.05544
State	Published - Feb 25 2015

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/eLife.05544

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Lin, M. I., Price, E. N., Boatman, S., Hagedorn, E. J., Trompouki, E., Satishchandran, S., Carspecken, C. W., Uong, A., DiBiase, A., Yang, S., Canver, M. C., Dahlberg, A., Lu, Z., Zhang, C., Orkin, S. H., Bernstein, I. D., Aster, J. C., White, R. M., & Zon, L. I. (2015). Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling. eLife, 2015(4), Article e05544. https://doi.org/10.7554/eLife.05544

Lin, MI, Price, EN, Boatman, S, Hagedorn, EJ, Trompouki, E, Satishchandran, S, Carspecken, CW, Uong, A, DiBiase, A, Yang, S, Canver, MC, Dahlberg, A, Lu, Z, Zhang, C, Orkin, SH, Bernstein, ID, Aster, JC, White, RM & Zon, LI 2015, 'Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling', eLife, vol. 2015, no. 4, e05544. https://doi.org/10.7554/eLife.05544

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abstract = "Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. Here, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib) and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in Angptl2-stimulated CD34+ cells showed a strong Myc activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. Angptl2 can increase Notch activation in cultured cells and Angptl receptor interacted with Notch to regulate Notch cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets.",

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AU - Satishchandran, Sruthi

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AU - Uong, Audrey

AU - DiBiase, Anthony

AU - Yang, Song

AU - Canver, Matthew C.

AU - Dahlberg, Ann

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AU - Zhang, Chengcheng

AU - Orkin, Stuart H.

AU - Bernstein, Irwin D.

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AU - White, Richard M.

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AB - Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. Here, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib) and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in Angptl2-stimulated CD34+ cells showed a strong Myc activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. Angptl2 can increase Notch activation in cultured cells and Angptl receptor interacted with Notch to regulate Notch cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets.

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Angiopoietin-like proteins stimulate HSPC development through interaction with Notch receptor signaling

Abstract

ASJC Scopus subject areas

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