Improvement of postnatal neovascularization by human embryonic stem cell-derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia

Seung-Woo Cho, Sung Hwan Moon, Soo Hong Lee, Sun Woong Kang, Jumi Kim, Jae Min Lim, Hyo Soo Kim, Byung Soo Kim, Hyung Min Chung

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

BACKGROUND - We established an efficient preparation method to obtain endothelial-like cells (ECs) from human embryonic stem cells (hESCs) and tested whether these hESC-ECs would show therapeutic potential for treatment of hindlimb ischemia. METHODS AND RESULTS - ECs differentiated from hESCs were obtained by mechanical isolation and cell sorting for von Willebrand factor. The isolated hESC-ECs maintained endothelial cell-specific characteristics such as endothelial marker expression and capillary formation. One day after surgical induction of hindlimb ischemia in athymic mice, hESC-ECs were injected intramuscularly into ischemic limbs. Four weeks after treatment, hESC-EC treatment significantly increased limb salvage (36%) compared with treatment with medium (0%). In addition, laser Doppler imaging showed that the ratio of blood perfusion (ischemic to normal limb) was increased significantly (P<0.01) by hESC-EC treatment (0.511±0.167) compared with medium injection (0.073±0.061). Capillary and arteriole densities were 658±190/mm and 30±11/mm in the hESC-EC group, respectively, whereas those in the medium group were 392±118/mm and 16±8/mm, respectively (P<0.01). Reverse-transcription polymerase chain reaction with human-specific primers revealed mRNA expression of human endothelial markers and human angiogenic factors in ischemic mouse tissues. The transplanted hESC-ECs were localized as capillaries near muscle tissues in ischemic regions or incorporated in the vessels between muscle tissues, as confirmed by human nuclear antigen staining with platelet/endothelial cell adhesion molecule or von Willebrand factor. CONCLUSIONS - This study demonstrates that hESC-EC transplantation improves blood perfusion and limb salvage by facilitating postnatal neovascularization in a mouse model of hindlimb ischemia. Thus, hESC-ECs might be useful as an alternative cell source for angiogenic therapy.

Original languageEnglish
Pages (from-to)2409-2419
Number of pages11
JournalCirculation
Volume116
Issue number21
DOIs
Publication statusPublished - 2007 Nov 1

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Cell Transplantation
Hindlimb
Ischemia
Endothelial Cells
Limb Salvage
von Willebrand Factor
Human Embryonic Stem Cells
Therapeutics
Extremities
Perfusion
Muscles
Nuclear Antigens
Cell Separation
Angiogenesis Inducing Agents
Cell Adhesion Molecules
Arterioles
Nude Mice
Reverse Transcription
Lasers
Blood Platelets

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Cho, Seung-Woo ; Moon, Sung Hwan ; Lee, Soo Hong ; Kang, Sun Woong ; Kim, Jumi ; Lim, Jae Min ; Kim, Hyo Soo ; Kim, Byung Soo ; Chung, Hyung Min. / Improvement of postnatal neovascularization by human embryonic stem cell-derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. In: Circulation. 2007 ; Vol. 116, No. 21. pp. 2409-2419.
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Improvement of postnatal neovascularization by human embryonic stem cell-derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia. / Cho, Seung-Woo; Moon, Sung Hwan; Lee, Soo Hong; Kang, Sun Woong; Kim, Jumi; Lim, Jae Min; Kim, Hyo Soo; Kim, Byung Soo; Chung, Hyung Min.

In: Circulation, Vol. 116, No. 21, 01.11.2007, p. 2409-2419.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Improvement of postnatal neovascularization by human embryonic stem cell-derived endothelial-like cell transplantation in a mouse model of hindlimb ischemia

AU - Cho, Seung-Woo

AU - Moon, Sung Hwan

AU - Lee, Soo Hong

AU - Kang, Sun Woong

AU - Kim, Jumi

AU - Lim, Jae Min

AU - Kim, Hyo Soo

AU - Kim, Byung Soo

AU - Chung, Hyung Min

PY - 2007/11/1

Y1 - 2007/11/1

N2 - BACKGROUND - We established an efficient preparation method to obtain endothelial-like cells (ECs) from human embryonic stem cells (hESCs) and tested whether these hESC-ECs would show therapeutic potential for treatment of hindlimb ischemia. METHODS AND RESULTS - ECs differentiated from hESCs were obtained by mechanical isolation and cell sorting for von Willebrand factor. The isolated hESC-ECs maintained endothelial cell-specific characteristics such as endothelial marker expression and capillary formation. One day after surgical induction of hindlimb ischemia in athymic mice, hESC-ECs were injected intramuscularly into ischemic limbs. Four weeks after treatment, hESC-EC treatment significantly increased limb salvage (36%) compared with treatment with medium (0%). In addition, laser Doppler imaging showed that the ratio of blood perfusion (ischemic to normal limb) was increased significantly (P<0.01) by hESC-EC treatment (0.511±0.167) compared with medium injection (0.073±0.061). Capillary and arteriole densities were 658±190/mm and 30±11/mm in the hESC-EC group, respectively, whereas those in the medium group were 392±118/mm and 16±8/mm, respectively (P<0.01). Reverse-transcription polymerase chain reaction with human-specific primers revealed mRNA expression of human endothelial markers and human angiogenic factors in ischemic mouse tissues. The transplanted hESC-ECs were localized as capillaries near muscle tissues in ischemic regions or incorporated in the vessels between muscle tissues, as confirmed by human nuclear antigen staining with platelet/endothelial cell adhesion molecule or von Willebrand factor. CONCLUSIONS - This study demonstrates that hESC-EC transplantation improves blood perfusion and limb salvage by facilitating postnatal neovascularization in a mouse model of hindlimb ischemia. Thus, hESC-ECs might be useful as an alternative cell source for angiogenic therapy.

AB - BACKGROUND - We established an efficient preparation method to obtain endothelial-like cells (ECs) from human embryonic stem cells (hESCs) and tested whether these hESC-ECs would show therapeutic potential for treatment of hindlimb ischemia. METHODS AND RESULTS - ECs differentiated from hESCs were obtained by mechanical isolation and cell sorting for von Willebrand factor. The isolated hESC-ECs maintained endothelial cell-specific characteristics such as endothelial marker expression and capillary formation. One day after surgical induction of hindlimb ischemia in athymic mice, hESC-ECs were injected intramuscularly into ischemic limbs. Four weeks after treatment, hESC-EC treatment significantly increased limb salvage (36%) compared with treatment with medium (0%). In addition, laser Doppler imaging showed that the ratio of blood perfusion (ischemic to normal limb) was increased significantly (P<0.01) by hESC-EC treatment (0.511±0.167) compared with medium injection (0.073±0.061). Capillary and arteriole densities were 658±190/mm and 30±11/mm in the hESC-EC group, respectively, whereas those in the medium group were 392±118/mm and 16±8/mm, respectively (P<0.01). Reverse-transcription polymerase chain reaction with human-specific primers revealed mRNA expression of human endothelial markers and human angiogenic factors in ischemic mouse tissues. The transplanted hESC-ECs were localized as capillaries near muscle tissues in ischemic regions or incorporated in the vessels between muscle tissues, as confirmed by human nuclear antigen staining with platelet/endothelial cell adhesion molecule or von Willebrand factor. CONCLUSIONS - This study demonstrates that hESC-EC transplantation improves blood perfusion and limb salvage by facilitating postnatal neovascularization in a mouse model of hindlimb ischemia. Thus, hESC-ECs might be useful as an alternative cell source for angiogenic therapy.

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