SOX17 Regulates Conversion of Human Fibroblasts into Endothelial Cells and Erythroblasts by Dedifferentiation into CD34+ Progenitor Cells

Lianghui Zhang, Ankit Jambusaria, Zhigang Hong, Glenn Marsboom, Peter T. Toth, Brittney-Shea Herbert, Asrar B. Malik, Jalees Rehman

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. Methods: CD34+ progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34+ cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Results: Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34+ progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Conclusions: Dedifferentiation of fibroblasts to intermediate CD34+ progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34+ progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.

Original languageEnglish (US)
Pages (from-to)2505-2523
Number of pages19
JournalCirculation
Volume135
Issue number25
DOIs
StatePublished - Jun 20 2017
Externally publishedYes

Fingerprint

Cell Dedifferentiation
Erythroblasts
Stem Cells
Endothelial Cells
Fibroblasts
SOXF Transcription Factors
Up-Regulation
Erythrocytes
Myocardial Infarction
Severe Combined Immunodeficiency
Erythroid Cells
Telomerase
Teratoma
Cell Lineage
Microvessels
Embryonic Development
Blood Vessels
Intercellular Signaling Peptides and Proteins
Transcription Factors
Theoretical Models

Keywords

  • aging
  • angiogenesis
  • dedifferentiation
  • development
  • endothelial cells
  • erythropoiesis
  • fibroblasts
  • myocardial infarction
  • progenitor cells
  • regeneration
  • reprogramming
  • SOX17
  • telomerase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

SOX17 Regulates Conversion of Human Fibroblasts into Endothelial Cells and Erythroblasts by Dedifferentiation into CD34+ Progenitor Cells. / Zhang, Lianghui; Jambusaria, Ankit; Hong, Zhigang; Marsboom, Glenn; Toth, Peter T.; Herbert, Brittney-Shea; Malik, Asrar B.; Rehman, Jalees.

In: Circulation, Vol. 135, No. 25, 20.06.2017, p. 2505-2523.

Research output: Contribution to journalArticle

Zhang, Lianghui ; Jambusaria, Ankit ; Hong, Zhigang ; Marsboom, Glenn ; Toth, Peter T. ; Herbert, Brittney-Shea ; Malik, Asrar B. ; Rehman, Jalees. / SOX17 Regulates Conversion of Human Fibroblasts into Endothelial Cells and Erythroblasts by Dedifferentiation into CD34+ Progenitor Cells. In: Circulation. 2017 ; Vol. 135, No. 25. pp. 2505-2523.
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abstract = "Background: The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. Methods: CD34+ progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34+ cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Results: Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34+ progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Conclusions: Dedifferentiation of fibroblasts to intermediate CD34+ progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34+ progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.",
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T1 - SOX17 Regulates Conversion of Human Fibroblasts into Endothelial Cells and Erythroblasts by Dedifferentiation into CD34+ Progenitor Cells

AU - Zhang, Lianghui

AU - Jambusaria, Ankit

AU - Hong, Zhigang

AU - Marsboom, Glenn

AU - Toth, Peter T.

AU - Herbert, Brittney-Shea

AU - Malik, Asrar B.

AU - Rehman, Jalees

PY - 2017/6/20

Y1 - 2017/6/20

N2 - Background: The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. Methods: CD34+ progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34+ cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Results: Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34+ progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Conclusions: Dedifferentiation of fibroblasts to intermediate CD34+ progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34+ progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.

AB - Background: The mechanisms underlying the dedifferentiation and lineage conversion of adult human fibroblasts into functional endothelial cells have not yet been fully defined. Furthermore, it is not known whether fibroblast dedifferentiation recapitulates the generation of multipotent progenitors during embryonic development, which give rise to endothelial and hematopoietic cell lineages. Here we established the role of the developmental transcription factor SOX17 in regulating the bilineage conversion of fibroblasts by the generation of intermediate progenitors. Methods: CD34+ progenitors were generated after the dedifferentiation of human adult dermal fibroblasts by overexpression of pluripotency transcription factors. Sorted CD34+ cells were transdifferentiated into induced endothelial cells and induced erythroblasts using lineage-specific growth factors. The therapeutic potential of the generated cells was assessed in an experimental model of myocardial infarction. Results: Induced endothelial cells expressed specific endothelial cell surface markers and also exhibited the capacity for cell proliferation and neovascularization. Induced erythroblasts expressed erythroid surface markers and formed erythroid colonies. Endothelial lineage conversion was dependent on the upregulation of the developmental transcription factor SOX17, whereas suppression of SOX17 instead directed the cells toward an erythroid fate. Implantation of these human bipotential CD34+ progenitors into nonobese diabetic/severe combined immunodeficiency (NOD-SCID) mice resulted in the formation of microvessels derived from human fibroblasts perfused with mouse and human erythrocytes. Endothelial cells generated from human fibroblasts also showed upregulation of telomerase. Cell implantation markedly improved vascularity and cardiac function after myocardial infarction without any evidence of teratoma formation. Conclusions: Dedifferentiation of fibroblasts to intermediate CD34+ progenitors gives rise to endothelial cells and erythroblasts in a SOX17-dependent manner. These findings identify the intermediate CD34+ progenitor state as a critical bifurcation point, which can be tuned to generate functional blood vessels or erythrocytes and salvage ischemic tissue.

KW - aging

KW - angiogenesis

KW - dedifferentiation

KW - development

KW - endothelial cells

KW - erythropoiesis

KW - fibroblasts

KW - myocardial infarction

KW - progenitor cells

KW - regeneration

KW - reprogramming

KW - SOX17

KW - telomerase

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U2 - 10.1161/CIRCULATIONAHA.116.025722

DO - 10.1161/CIRCULATIONAHA.116.025722

M3 - Article

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SP - 2505

EP - 2523

JO - Circulation

JF - Circulation

SN - 0009-7322

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