Selective recruitment of endothelial progenitor cells to ischemic tissues with increased neovascularization

Sanghoon Park, Oren M. Tepper, Robert D. Galiano, Jennifer M. Capla, Samuel Baharestani, Mark E. Kleinman, Catherine R. Pelo, Jamie P. Levine, Geoffrey C. Gurtner

Research output: Contribution to journalArticle

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Abstract

Tissue ischemia remains a common problem in plastic surgery and one for which proangiogenic approaches have been investigated. Given the recent discovery of circulating endothelial stem or progenitor cells that are able to form new blood vessels, the authors sought to determine whether these cells might selectively traffic to regions of tissue ischemia and induce neovascularization. Endothelial progenitor cells were isolated from the peripheral blood of healthy human volunteers and expanded ex vivo for 7 days. Elevation of a cranially based random-pattern skin flap was performed in nude mice, after which they were injected with fluorescent-labeled endothelial progenitor cells (5 × 105; n = 15), fluorescent-labeled human microvascular endothelial cells (5 × 105; n= 15), or media alone (n = 15). Histologic examination demonstrated that endothelial progenitor cells were recruited to ischemic tissue and first appeared by postoperative day 3. Subsequently, endothelial progenitor cell numbers increased exponentially over time for the remainder of the study [0 cells/mm2 at day 0 (n = 3), 9.6 ± 0.9 cells/mm2 at day 3 (n = 3), 24.6 ± 1.5 cells/mm2 at day 7 (n = 3), and 196.3 ± 9.6 cells/mm 2 at day 14 (n = 9)]. At all time points, endothelial progenitor cells localized preferentially to ischemic tissue and healing wound edges, and were not observed in normal, uninjured tissues. Endothelial progenitor cell transplantation led to a statistically significant increase in vascular density in ischemic tissues by postoperative day 14 [28.7 ± 1.2 in the endothelial progenitor cell group (n = 9) versus 18 ± 1.1 in the control media group (n = 9) and 17.7 ± 1.0 in the human microvascular endothelial cell group (n = 9; p < 0.01)]. Endothelial progenitor cell transplantation also showed trends toward increased flap survival [171.2 ± 18 mm 2 in the endothelial progenitor cell group (n = 12) versus 134.2 ± 10 mm2 in the media group (n = 12) and 145.0 ± 13 mm2 in the human microvascular endothelial cell group (n = 12)], but this did not reach statistical significance. These findings indicate that local tissue ischemia is a potent stimulus for the recruitment of circulating endothelial progenitor cells. Systemic delivery of endothelial progenitor cells increased neovascularization and suggests that autologous endothelial progenitor cell transplantation may have a role in the salvage of ischemic tissue.

Original languageEnglish (US)
Pages (from-to)284-293
Number of pages10
JournalPlastic and Reconstructive Surgery
Volume113
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

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Cell Transplantation
Endothelial Cells
Ischemia
Blood Vessels
Endothelial Progenitor Cells
Stem Cells
Plastic Surgery
Nude Mice
Wound Healing
Healthy Volunteers
Cell Count
Control Groups
Skin
Survival

ASJC Scopus subject areas

  • Surgery

Cite this

Selective recruitment of endothelial progenitor cells to ischemic tissues with increased neovascularization. / Park, Sanghoon; Tepper, Oren M.; Galiano, Robert D.; Capla, Jennifer M.; Baharestani, Samuel; Kleinman, Mark E.; Pelo, Catherine R.; Levine, Jamie P.; Gurtner, Geoffrey C.

In: Plastic and Reconstructive Surgery, Vol. 113, No. 1, 01.2004, p. 284-293.

Research output: Contribution to journalArticle

Park, S, Tepper, OM, Galiano, RD, Capla, JM, Baharestani, S, Kleinman, ME, Pelo, CR, Levine, JP & Gurtner, GC 2004, 'Selective recruitment of endothelial progenitor cells to ischemic tissues with increased neovascularization', Plastic and Reconstructive Surgery, vol. 113, no. 1, pp. 284-293. https://doi.org/10.1097/01.PRS.0000091169.51035.A5
Park, Sanghoon ; Tepper, Oren M. ; Galiano, Robert D. ; Capla, Jennifer M. ; Baharestani, Samuel ; Kleinman, Mark E. ; Pelo, Catherine R. ; Levine, Jamie P. ; Gurtner, Geoffrey C. / Selective recruitment of endothelial progenitor cells to ischemic tissues with increased neovascularization. In: Plastic and Reconstructive Surgery. 2004 ; Vol. 113, No. 1. pp. 284-293.
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abstract = "Tissue ischemia remains a common problem in plastic surgery and one for which proangiogenic approaches have been investigated. Given the recent discovery of circulating endothelial stem or progenitor cells that are able to form new blood vessels, the authors sought to determine whether these cells might selectively traffic to regions of tissue ischemia and induce neovascularization. Endothelial progenitor cells were isolated from the peripheral blood of healthy human volunteers and expanded ex vivo for 7 days. Elevation of a cranially based random-pattern skin flap was performed in nude mice, after which they were injected with fluorescent-labeled endothelial progenitor cells (5 × 105; n = 15), fluorescent-labeled human microvascular endothelial cells (5 × 105; n= 15), or media alone (n = 15). Histologic examination demonstrated that endothelial progenitor cells were recruited to ischemic tissue and first appeared by postoperative day 3. Subsequently, endothelial progenitor cell numbers increased exponentially over time for the remainder of the study [0 cells/mm2 at day 0 (n = 3), 9.6 ± 0.9 cells/mm2 at day 3 (n = 3), 24.6 ± 1.5 cells/mm2 at day 7 (n = 3), and 196.3 ± 9.6 cells/mm 2 at day 14 (n = 9)]. At all time points, endothelial progenitor cells localized preferentially to ischemic tissue and healing wound edges, and were not observed in normal, uninjured tissues. Endothelial progenitor cell transplantation led to a statistically significant increase in vascular density in ischemic tissues by postoperative day 14 [28.7 ± 1.2 in the endothelial progenitor cell group (n = 9) versus 18 ± 1.1 in the control media group (n = 9) and 17.7 ± 1.0 in the human microvascular endothelial cell group (n = 9; p < 0.01)]. Endothelial progenitor cell transplantation also showed trends toward increased flap survival [171.2 ± 18 mm 2 in the endothelial progenitor cell group (n = 12) versus 134.2 ± 10 mm2 in the media group (n = 12) and 145.0 ± 13 mm2 in the human microvascular endothelial cell group (n = 12)], but this did not reach statistical significance. These findings indicate that local tissue ischemia is a potent stimulus for the recruitment of circulating endothelial progenitor cells. Systemic delivery of endothelial progenitor cells increased neovascularization and suggests that autologous endothelial progenitor cell transplantation may have a role in the salvage of ischemic tissue.",
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AU - Tepper, Oren M.

AU - Galiano, Robert D.

AU - Capla, Jennifer M.

AU - Baharestani, Samuel

AU - Kleinman, Mark E.

AU - Pelo, Catherine R.

AU - Levine, Jamie P.

AU - Gurtner, Geoffrey C.

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N2 - Tissue ischemia remains a common problem in plastic surgery and one for which proangiogenic approaches have been investigated. Given the recent discovery of circulating endothelial stem or progenitor cells that are able to form new blood vessels, the authors sought to determine whether these cells might selectively traffic to regions of tissue ischemia and induce neovascularization. Endothelial progenitor cells were isolated from the peripheral blood of healthy human volunteers and expanded ex vivo for 7 days. Elevation of a cranially based random-pattern skin flap was performed in nude mice, after which they were injected with fluorescent-labeled endothelial progenitor cells (5 × 105; n = 15), fluorescent-labeled human microvascular endothelial cells (5 × 105; n= 15), or media alone (n = 15). Histologic examination demonstrated that endothelial progenitor cells were recruited to ischemic tissue and first appeared by postoperative day 3. Subsequently, endothelial progenitor cell numbers increased exponentially over time for the remainder of the study [0 cells/mm2 at day 0 (n = 3), 9.6 ± 0.9 cells/mm2 at day 3 (n = 3), 24.6 ± 1.5 cells/mm2 at day 7 (n = 3), and 196.3 ± 9.6 cells/mm 2 at day 14 (n = 9)]. At all time points, endothelial progenitor cells localized preferentially to ischemic tissue and healing wound edges, and were not observed in normal, uninjured tissues. Endothelial progenitor cell transplantation led to a statistically significant increase in vascular density in ischemic tissues by postoperative day 14 [28.7 ± 1.2 in the endothelial progenitor cell group (n = 9) versus 18 ± 1.1 in the control media group (n = 9) and 17.7 ± 1.0 in the human microvascular endothelial cell group (n = 9; p < 0.01)]. Endothelial progenitor cell transplantation also showed trends toward increased flap survival [171.2 ± 18 mm 2 in the endothelial progenitor cell group (n = 12) versus 134.2 ± 10 mm2 in the media group (n = 12) and 145.0 ± 13 mm2 in the human microvascular endothelial cell group (n = 12)], but this did not reach statistical significance. These findings indicate that local tissue ischemia is a potent stimulus for the recruitment of circulating endothelial progenitor cells. Systemic delivery of endothelial progenitor cells increased neovascularization and suggests that autologous endothelial progenitor cell transplantation may have a role in the salvage of ischemic tissue.

AB - Tissue ischemia remains a common problem in plastic surgery and one for which proangiogenic approaches have been investigated. Given the recent discovery of circulating endothelial stem or progenitor cells that are able to form new blood vessels, the authors sought to determine whether these cells might selectively traffic to regions of tissue ischemia and induce neovascularization. Endothelial progenitor cells were isolated from the peripheral blood of healthy human volunteers and expanded ex vivo for 7 days. Elevation of a cranially based random-pattern skin flap was performed in nude mice, after which they were injected with fluorescent-labeled endothelial progenitor cells (5 × 105; n = 15), fluorescent-labeled human microvascular endothelial cells (5 × 105; n= 15), or media alone (n = 15). Histologic examination demonstrated that endothelial progenitor cells were recruited to ischemic tissue and first appeared by postoperative day 3. Subsequently, endothelial progenitor cell numbers increased exponentially over time for the remainder of the study [0 cells/mm2 at day 0 (n = 3), 9.6 ± 0.9 cells/mm2 at day 3 (n = 3), 24.6 ± 1.5 cells/mm2 at day 7 (n = 3), and 196.3 ± 9.6 cells/mm 2 at day 14 (n = 9)]. At all time points, endothelial progenitor cells localized preferentially to ischemic tissue and healing wound edges, and were not observed in normal, uninjured tissues. Endothelial progenitor cell transplantation led to a statistically significant increase in vascular density in ischemic tissues by postoperative day 14 [28.7 ± 1.2 in the endothelial progenitor cell group (n = 9) versus 18 ± 1.1 in the control media group (n = 9) and 17.7 ± 1.0 in the human microvascular endothelial cell group (n = 9; p < 0.01)]. Endothelial progenitor cell transplantation also showed trends toward increased flap survival [171.2 ± 18 mm 2 in the endothelial progenitor cell group (n = 12) versus 134.2 ± 10 mm2 in the media group (n = 12) and 145.0 ± 13 mm2 in the human microvascular endothelial cell group (n = 12)], but this did not reach statistical significance. These findings indicate that local tissue ischemia is a potent stimulus for the recruitment of circulating endothelial progenitor cells. Systemic delivery of endothelial progenitor cells increased neovascularization and suggests that autologous endothelial progenitor cell transplantation may have a role in the salvage of ischemic tissue.

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