Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2

Sangho Lee, Changwon Park, Ji Woong Han, Ju Young Kim, Kyuwon Cho, Eun Jae Kim, Sangsung Kim, Shin Jeong Lee, Se Yeong Oh, Yoshiaki Tanaka, In Hyun Park, Hyo Jae An, Claire Min Shin, Shraya Sharma, Young Sup Yoon

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Rationale: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. Objective: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. Methods and Results: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. Conclusions: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process.

Original languageEnglish
Pages (from-to)848-861
Number of pages14
JournalCirculation Research
Volume120
Issue number5
DOIs
Publication statusPublished - 2017 Mar 3

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Endothelial Cells
Fibroblasts
Skin
Hindlimb
Cell- and Tissue-Based Therapy
Transgenes
Transcription Factors
Stem Cells
Ischemia
Phenotype
Vascular Endothelial Growth Factor Receptor-2
Regenerative Medicine
Blood Vessels
Therapeutics

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Lee, Sangho ; Park, Changwon ; Han, Ji Woong ; Kim, Ju Young ; Cho, Kyuwon ; Kim, Eun Jae ; Kim, Sangsung ; Lee, Shin Jeong ; Oh, Se Yeong ; Tanaka, Yoshiaki ; Park, In Hyun ; An, Hyo Jae ; Shin, Claire Min ; Sharma, Shraya ; Yoon, Young Sup. / Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2. In: Circulation Research. 2017 ; Vol. 120, No. 5. pp. 848-861.
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title = "Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2",
abstract = "Rationale: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. Objective: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. Methods and Results: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. Conclusions: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process.",
author = "Sangho Lee and Changwon Park and Han, {Ji Woong} and Kim, {Ju Young} and Kyuwon Cho and Kim, {Eun Jae} and Sangsung Kim and Lee, {Shin Jeong} and Oh, {Se Yeong} and Yoshiaki Tanaka and Park, {In Hyun} and An, {Hyo Jae} and Shin, {Claire Min} and Shraya Sharma and Yoon, {Young Sup}",
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Lee, S, Park, C, Han, JW, Kim, JY, Cho, K, Kim, EJ, Kim, S, Lee, SJ, Oh, SY, Tanaka, Y, Park, IH, An, HJ, Shin, CM, Sharma, S & Yoon, YS 2017, 'Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2', Circulation Research, vol. 120, no. 5, pp. 848-861. https://doi.org/10.1161/CIRCRESAHA.116.309833

Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2. / Lee, Sangho; Park, Changwon; Han, Ji Woong; Kim, Ju Young; Cho, Kyuwon; Kim, Eun Jae; Kim, Sangsung; Lee, Shin Jeong; Oh, Se Yeong; Tanaka, Yoshiaki; Park, In Hyun; An, Hyo Jae; Shin, Claire Min; Sharma, Shraya; Yoon, Young Sup.

In: Circulation Research, Vol. 120, No. 5, 03.03.2017, p. 848-861.

Research output: Contribution to journalArticle

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T1 - Direct Reprogramming of Human Dermal Fibroblasts into Endothelial Cells Using ER71/ETV2

AU - Lee, Sangho

AU - Park, Changwon

AU - Han, Ji Woong

AU - Kim, Ju Young

AU - Cho, Kyuwon

AU - Kim, Eun Jae

AU - Kim, Sangsung

AU - Lee, Shin Jeong

AU - Oh, Se Yeong

AU - Tanaka, Yoshiaki

AU - Park, In Hyun

AU - An, Hyo Jae

AU - Shin, Claire Min

AU - Sharma, Shraya

AU - Yoon, Young Sup

PY - 2017/3/3

Y1 - 2017/3/3

N2 - Rationale: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. Objective: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. Methods and Results: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. Conclusions: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process.

AB - Rationale: Direct conversion or reprogramming of human postnatal cells into endothelial cells (ECs), bypassing stem or progenitor cell status, is crucial for regenerative medicine, cell therapy, and pathophysiological investigation but has remained largely unexplored. Objective: We sought to directly reprogram human postnatal dermal fibroblasts to ECs with vasculogenic and endothelial transcription factors and determine their vascularizing and therapeutic potential. Methods and Results: We utilized various combinations of 7 EC transcription factors to transduce human postnatal dermal fibroblasts and found that ER71/ETV2 (ETS variant 2) alone best induced endothelial features. KDR+ (kinase insert domain receptor) cells sorted at day 7 from ER71/ETV2-transduced human postnatal dermal fibroblasts showed less mature but enriched endothelial characteristics and thus were referred to as early reprogrammed ECs (rECs), and did not undergo maturation by further culture. After a period of several weeks' transgene-free culture followed by transient reinduction of ER71/ETV2, early rECs matured during 3 months of culture and showed reduced ETV2 expression, reaching a mature phenotype similar to postnatal human ECs. These were termed late rECs. While early rECs exhibited an immature phenotype, their implantation into ischemic hindlimbs induced enhanced recovery from ischemia. These 2 rECs showed clear capacity for contributing to new vessel formation through direct vascular incorporation in vivo. Paracrine or proangiogenic effects of implanted early rECs played a significant role in repairing hindlimb ischemia. Conclusions: This study for the first time demonstrates that ER71/ETV2 alone can directly reprogram human postnatal cells to functional, mature ECs after an intervening transgene-free period. These rECs could be valuable for cell therapy, personalized disease investigation, and exploration of the reprogramming process.

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