Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction

Rosalinda Madonna, Lyubomir Petrov, Maria Anna Teberino, Lamberto Manzoli, Jean Pierre Karam, Francesca Vera Renna, Peter Ferdinandy, Claudia N. Montero-Menei, Seppo Ylä-Herttuala, Raffaele De Caterina

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Abstract

Rationale Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. Aims We examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). Methods and results We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve-month-old C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 μL, n = 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 105 cells/20 μL, n = 5), or concentrated medium (CM) from AT-MSCs (20 μL, n = 8), or AT-MSCs (2.5 × 105 cells/20 μL) conjugated with empty PAMs (n = 7), or VEGF-releasing PAMs (n = 8). Sham-operated mice (n = 7) were used as controls. VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. Conclusions AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.

Original languageEnglish
Pages (from-to)39-49
Number of pages11
JournalCardiovascular Research
Volume108
Issue number1
DOIs
Publication statusPublished - May 21 2015

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Mesenchymal Stromal Cells
Vascular Endothelial Growth Factor A
Adipose Tissue
Transplantation
Myocardial Infarction
Apoptosis
Cellular Microenvironment
Injections
Stromal Cells
Fibronectins
Ligation
Coronary Vessels
Fibrosis
Stem Cells

Keywords

  • Adipose tissue-derived mesenchymal stromal cells
  • Microspheres
  • Myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction. / Madonna, Rosalinda; Petrov, Lyubomir; Teberino, Maria Anna; Manzoli, Lamberto; Karam, Jean Pierre; Renna, Francesca Vera; Ferdinandy, Peter; Montero-Menei, Claudia N.; Ylä-Herttuala, Seppo; De Caterina, Raffaele.

In: Cardiovascular Research, Vol. 108, No. 1, 21.05.2015, p. 39-49.

Research output: Contribution to journalArticle

Madonna, R, Petrov, L, Teberino, MA, Manzoli, L, Karam, JP, Renna, FV, Ferdinandy, P, Montero-Menei, CN, Ylä-Herttuala, S & De Caterina, R 2015, 'Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction', Cardiovascular Research, vol. 108, no. 1, pp. 39-49. https://doi.org/10.1093/cvr/cvv197
Madonna, Rosalinda ; Petrov, Lyubomir ; Teberino, Maria Anna ; Manzoli, Lamberto ; Karam, Jean Pierre ; Renna, Francesca Vera ; Ferdinandy, Peter ; Montero-Menei, Claudia N. ; Ylä-Herttuala, Seppo ; De Caterina, Raffaele. / Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction. In: Cardiovascular Research. 2015 ; Vol. 108, No. 1. pp. 39-49.
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abstract = "Rationale Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. Aims We examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). Methods and results We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve-month-old C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 μL, n = 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 105 cells/20 μL, n = 5), or concentrated medium (CM) from AT-MSCs (20 μL, n = 8), or AT-MSCs (2.5 × 105 cells/20 μL) conjugated with empty PAMs (n = 7), or VEGF-releasing PAMs (n = 8). Sham-operated mice (n = 7) were used as controls. VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. Conclusions AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.",
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AU - Madonna, Rosalinda

AU - Petrov, Lyubomir

AU - Teberino, Maria Anna

AU - Manzoli, Lamberto

AU - Karam, Jean Pierre

AU - Renna, Francesca Vera

AU - Ferdinandy, Peter

AU - Montero-Menei, Claudia N.

AU - Ylä-Herttuala, Seppo

AU - De Caterina, Raffaele

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N2 - Rationale Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. Aims We examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). Methods and results We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve-month-old C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 μL, n = 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 105 cells/20 μL, n = 5), or concentrated medium (CM) from AT-MSCs (20 μL, n = 8), or AT-MSCs (2.5 × 105 cells/20 μL) conjugated with empty PAMs (n = 7), or VEGF-releasing PAMs (n = 8). Sham-operated mice (n = 7) were used as controls. VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. Conclusions AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.

AB - Rationale Engraftment and survival of transplanted stem or stromal cells in the microenvironment of host tissues may be improved by combining such cells with scaffolds to delay apoptosis and enhance regenerative properties. Aims We examined whether poly(lactic-co-glycolic acid) pharmacologically active microcarriers (PAMs) releasing vascular endothelial growth factor (VEGF) enhance survival, differentiation, and angiogenesis of adipose tissue-mesenchymal stromal cells (AT-MSCs). We analysed the efficacy of transplanted AT-MSCs conjugated with PAMs in a murine model of acute myocardial infarction (AMI). Methods and results We used fibronectin-coated (empty) PAMs or VEGF-releasing PAMs covered with murine AT-MSCs. Twelve-month-old C57 mice underwent coronary artery ligation to induce AMI, and were randomized into five treatment groups: AMI control (saline 20 μL, n = 7), AMI followed by intramyocardial injection with AT-MSCs (2.5 × 105 cells/20 μL, n = 5), or concentrated medium (CM) from AT-MSCs (20 μL, n = 8), or AT-MSCs (2.5 × 105 cells/20 μL) conjugated with empty PAMs (n = 7), or VEGF-releasing PAMs (n = 8). Sham-operated mice (n = 7) were used as controls. VEGF-releasing PAMs increased proliferation and angiogenic potential of AT-MSCs, but did not impact their osteogenic or adipogenic differentiation. AT-MSCs conjugated with VEGF-releasing PAMs inhibited apoptosis, decreased fibrosis, increased arteriogenesis and the number of cardiac-resident Ki-67 positive cells, and improved myocardial fractional shortening compared with AT-MSCs alone when transplanted into the infarcted hearts of C57 mice. With the exception of fractional shortening, all such effects of AT-MSCs conjugated with VEGF-PAMs were paralleled by the injection of CM. Conclusions AT-MSCs conjugated with VEGF-releasing PAMs exert paracrine effects that may have therapeutic applications.

KW - Adipose tissue-derived mesenchymal stromal cells

KW - Microspheres

KW - Myocardial infarction

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