Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia

Phuc Van Pham, Ngoc Bich Vu, Hoa Trong Nguyen, Oanh Thuy Huynh, Mai Thi-Hoang Truong, T Bogoslovsky, RG Shaffer, D Tasev, E Colombo, T Asahara, P Donndorf, YY Bai, SW Kim, J Kim, EB Peters, PV Phuc, CH Hu, CH Hu, A Schuh, C KalkaA Kawamoto, W Suh, SK Cha, C Haller, DW Losordo, DW Losordo, DW Losordo, SH Li, Q She, JX Yu, A Flex, T Asahara, C Kalka, JM Isner, MC Yoder, MP White, L Wang, SJ Park, EA Kimbrel, R Lanza, OE Simonson, A Margariti, J Li, JK Han, R Morita, M Ginsberg, X Shi, MO Schupp, C Park, S Foja, H Shimada, Y Yoshida, K Iida, WK Nahm, L Zhou, V Falanga, F Liu, AN Behrens, I Elcheva, AG Lindgren, MB Veldman, S Lin, MP Craig, Z Zhang, J Jackson, A Minchenko, C Hitchon, DS Steinbrech, DS Steinbrech, EY Lee, J Rehman

Research output: Chapter in Book/Report/Conference proceedingChapter

11 Citations (Scopus)

Abstract

Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs. Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 % oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs. Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 ± 0.61 % in normoxia conditions to 7.52 ± 2.31 % in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro. Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia.
Original languageEnglish
Title of host publicationStem Cell Research & Therapy
PublisherBioMed Central
Pages104
Number of pages1
ISBN (Print)1328701603
DOIs
Publication statusPublished - 04 Dec 2016

Publication series

NameStem Cell Research & Therapy
Volume7

Fingerprint

Cell Hypoxia
Fibroblasts
Phenotype
Umbilicus
Foreskin
Cell Transplantation
Hindlimb
erucylphosphocholine
Ischemia
Endothelial Cells
Myocardial Infarction
Hypoxia
Oxygen
Skin
Therapeutics
Genes

Keywords

  • Cell Biology
  • Stem Cells

Cite this

Van Pham, P., Vu, N. B., Nguyen, H. T., Huynh, O. T., Truong, M. T-H., Bogoslovsky, T., ... Rehman, J. (2016). Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. In Stem Cell Research & Therapy (pp. 104). (Stem Cell Research & Therapy; Vol. 7). BioMed Central. https://doi.org/10.1186/s13287-016-0368-2
Van Pham, Phuc ; Vu, Ngoc Bich ; Nguyen, Hoa Trong ; Huynh, Oanh Thuy ; Truong, Mai Thi-Hoang ; Bogoslovsky, T ; Shaffer, RG ; Tasev, D ; Colombo, E ; Asahara, T ; Donndorf, P ; Bai, YY ; Kim, SW ; Kim, J ; Peters, EB ; Phuc, PV ; Hu, CH ; Hu, CH ; Schuh, A ; Kalka, C ; Kawamoto, A ; Suh, W ; Cha, SK ; Haller, C ; Losordo, DW ; Losordo, DW ; Losordo, DW ; Li, SH ; She, Q ; Yu, JX ; Flex, A ; Asahara, T ; Kalka, C ; Isner, JM ; Yoder, MC ; White, MP ; Wang, L ; Park, SJ ; Kimbrel, EA ; Lanza, R ; Simonson, OE ; Margariti, A ; Li, J ; Han, JK ; Morita, R ; Ginsberg, M ; Shi, X ; Schupp, MO ; Park, C ; Foja, S ; Shimada, H ; Yoshida, Y ; Iida, K ; Nahm, WK ; Zhou, L ; Falanga, V ; Liu, F ; Behrens, AN ; Elcheva, I ; Lindgren, AG ; Veldman, MB ; Lin, S ; Craig, MP ; Zhang, Z ; Jackson, J ; Minchenko, A ; Hitchon, C ; Steinbrech, DS ; Steinbrech, DS ; Lee, EY ; Rehman, J. / Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. Stem Cell Research & Therapy. BioMed Central, 2016. pp. 104 (Stem Cell Research & Therapy).
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abstract = "Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs. Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 {\%} oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs. Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 ± 0.61 {\%} in normoxia conditions to 7.52 ± 2.31 {\%} in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro. Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia.",
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Van Pham, P, Vu, NB, Nguyen, HT, Huynh, OT, Truong, MT-H, Bogoslovsky, T, Shaffer, RG, Tasev, D, Colombo, E, Asahara, T, Donndorf, P, Bai, YY, Kim, SW, Kim, J, Peters, EB, Phuc, PV, Hu, CH, Hu, CH, Schuh, A, Kalka, C, Kawamoto, A, Suh, W, Cha, SK, Haller, C, Losordo, DW, Losordo, DW, Losordo, DW, Li, SH, She, Q, Yu, JX, Flex, A, Asahara, T, Kalka, C, Isner, JM, Yoder, MC, White, MP, Wang, L, Park, SJ, Kimbrel, EA, Lanza, R, Simonson, OE, Margariti, A, Li, J, Han, JK, Morita, R, Ginsberg, M, Shi, X, Schupp, MO, Park, C, Foja, S, Shimada, H, Yoshida, Y, Iida, K, Nahm, WK, Zhou, L, Falanga, V, Liu, F, Behrens, AN, Elcheva, I, Lindgren, AG, Veldman, MB, Lin, S, Craig, MP, Zhang, Z, Jackson, J, Minchenko, A, Hitchon, C, Steinbrech, DS, Steinbrech, DS, Lee, EY & Rehman, J 2016, Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. in Stem Cell Research & Therapy. Stem Cell Research & Therapy, vol. 7, BioMed Central, pp. 104. https://doi.org/10.1186/s13287-016-0368-2

Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. / Van Pham, Phuc; Vu, Ngoc Bich; Nguyen, Hoa Trong; Huynh, Oanh Thuy; Truong, Mai Thi-Hoang; Bogoslovsky, T; Shaffer, RG; Tasev, D; Colombo, E; Asahara, T; Donndorf, P; Bai, YY; Kim, SW; Kim, J; Peters, EB; Phuc, PV; Hu, CH; Hu, CH; Schuh, A; Kalka, C; Kawamoto, A; Suh, W; Cha, SK; Haller, C; Losordo, DW; Losordo, DW; Losordo, DW; Li, SH; She, Q; Yu, JX; Flex, A; Asahara, T; Kalka, C; Isner, JM; Yoder, MC; White, MP; Wang, L; Park, SJ; Kimbrel, EA; Lanza, R; Simonson, OE; Margariti, A; Li, J; Han, JK; Morita, R; Ginsberg, M; Shi, X; Schupp, MO; Park, C; Foja, S; Shimada, H; Yoshida, Y; Iida, K; Nahm, WK; Zhou, L; Falanga, V; Liu, F; Behrens, AN; Elcheva, I; Lindgren, AG; Veldman, MB; Lin, S; Craig, MP; Zhang, Z; Jackson, J; Minchenko, A; Hitchon, C; Steinbrech, DS; Steinbrech, DS; Lee, EY; Rehman, J.

Stem Cell Research & Therapy. BioMed Central, 2016. p. 104 (Stem Cell Research & Therapy; Vol. 7).

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia

AU - Van Pham, Phuc

AU - Vu, Ngoc Bich

AU - Nguyen, Hoa Trong

AU - Huynh, Oanh Thuy

AU - Truong, Mai Thi-Hoang

AU - Bogoslovsky, T

AU - Shaffer, RG

AU - Tasev, D

AU - Colombo, E

AU - Asahara, T

AU - Donndorf, P

AU - Bai, YY

AU - Kim, SW

AU - Kim, J

AU - Peters, EB

AU - Phuc, PV

AU - Hu, CH

AU - Hu, CH

AU - Schuh, A

AU - Kalka, C

AU - Kawamoto, A

AU - Suh, W

AU - Cha, SK

AU - Haller, C

AU - Losordo, DW

AU - Losordo, DW

AU - Losordo, DW

AU - Li, SH

AU - She, Q

AU - Yu, JX

AU - Flex, A

AU - Asahara, T

AU - Kalka, C

AU - Isner, JM

AU - Yoder, MC

AU - White, MP

AU - Wang, L

AU - Park, SJ

AU - Kimbrel, EA

AU - Lanza, R

AU - Simonson, OE

AU - Margariti, A

AU - Li, J

AU - Han, JK

AU - Morita, R

AU - Ginsberg, M

AU - Shi, X

AU - Schupp, MO

AU - Park, C

AU - Foja, S

AU - Shimada, H

AU - Yoshida, Y

AU - Iida, K

AU - Nahm, WK

AU - Zhou, L

AU - Falanga, V

AU - Liu, F

AU - Behrens, AN

AU - Elcheva, I

AU - Lindgren, AG

AU - Veldman, MB

AU - Lin, S

AU - Craig, MP

AU - Zhang, Z

AU - Jackson, J

AU - Minchenko, A

AU - Hitchon, C

AU - Steinbrech, DS

AU - Steinbrech, DS

AU - Lee, EY

AU - Rehman, J

PY - 2016/12/4

Y1 - 2016/12/4

N2 - Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs. Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 % oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs. Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 ± 0.61 % in normoxia conditions to 7.52 ± 2.31 % in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro. Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia.

AB - Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs. Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 % oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs. Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 ± 0.61 % in normoxia conditions to 7.52 ± 2.31 % in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro. Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia.

KW - Cell Biology

KW - Stem Cells

U2 - 10.1186/s13287-016-0368-2

DO - 10.1186/s13287-016-0368-2

M3 - Chapter

C2 - 27488544

SN - 1328701603

T3 - Stem Cell Research & Therapy

SP - 104

BT - Stem Cell Research & Therapy

PB - BioMed Central

ER -

Van Pham P, Vu NB, Nguyen HT, Huynh OT, Truong MT-H, Bogoslovsky T et al. Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. In Stem Cell Research & Therapy. BioMed Central. 2016. p. 104. (Stem Cell Research & Therapy). https://doi.org/10.1186/s13287-016-0368-2