Tracking and therapeutic value of human adipose tissue-derived mesenchymal stem cell transplantation in reducing venous neointimal hyperplasia associated with arteriovenous fistula

Binxia Yang, Akshaar Brahmbhatt, Evelyn Nieves Torres, Brian Thielen, Deborah L. McCall, Sean Engel, Aditya Bansal, Mukesh Pandey, Allan B Dietz, Edward B Leof, Timothy R DeGrado, Debabrata Mukhopadhyay, Sanjay Misra

Research output: Contribution to journalArticle

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Abstract

Purpose: To determine if adventitial transplantation of human adipose tissue-derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1nu/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 (89Zr)-labeled MSCs serially with positron emission tomography (PET) for 21 days. Materials and Methods: All animal experiments were performed according to protocols approved by the institutional animal care and use committee. Fifty B6.Cg-Foxn1nu/J mice were used to accomplish the study aims. Green fluorescent protein was used to stably label 2.5 × 105 MSCs, which were injected into the adventitia of the outflow vein at the time of AVF creation in the MSC group. Eleven mice died after AVF placement. Animals were sacrificed on day 7 after AVF placement for real-time polymerase chain reaction (n = 6 for MSC and control groups) and histomorphometric (n = 6 for MSC and control groups) analyses and on day 21 for histomorphometric analysis only (n = 6 for MSC and control groups). In a separate group of experiments (n = 3), animals with transplanted 89Zrlabeled MSCs were serially imaged with PET for 3 weeks. Multiple comparisons were performed with two-way analysis of variance, followed by the Student t test with post hoc Bonferroni correction. Results: In vessels with transplanted MSCs compared with control vessels, there was a significant decrease in Mcp-1 gene expression (day 7: mean reduction, 62%; P =.029), with a significant increase in the mean lumen vessel area (day 7: mean increase, 176% [P =.013]; day 21: mean increase, 415% [P =.011]). Moreover, this was accompanied by a significant decrease in Ki-67 index (proliferation on day 7: mean reduction, 81% [P =.0003]; proliferation on day 21: mean reduction, 60%, [P =.016]). Prolonged retention of MSCs at the adventitia was evidenced by serial PET images of 89Zr-labeled cells. Conclusion: Adventitial transplantation of MSCs decreases Mcp-1 gene expression, accompanied by a reduction in venous neointimal hyperplasia.

Original languageEnglish (US)
Pages (from-to)513-522
Number of pages10
JournalRadiology
Volume279
Issue number2
DOIs
StatePublished - May 1 2016

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Mesenchymal Stem Cell Transplantation
Arteriovenous Fistula
Mesenchymal Stromal Cells
Hyperplasia
Adipose Tissue
Adventitia
Chemokine CCL2
Positron-Emission Tomography
Therapeutics
Gene Expression
Control Groups
Veins
Animal Care Committees
Green Fluorescent Proteins
Real-Time Polymerase Chain Reaction
Analysis of Variance
Transplantation

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Tracking and therapeutic value of human adipose tissue-derived mesenchymal stem cell transplantation in reducing venous neointimal hyperplasia associated with arteriovenous fistula. / Yang, Binxia; Brahmbhatt, Akshaar; Torres, Evelyn Nieves; Thielen, Brian; McCall, Deborah L.; Engel, Sean; Bansal, Aditya; Pandey, Mukesh; Dietz, Allan B; Leof, Edward B; DeGrado, Timothy R; Mukhopadhyay, Debabrata; Misra, Sanjay.

In: Radiology, Vol. 279, No. 2, 01.05.2016, p. 513-522.

Research output: Contribution to journalArticle

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title = "Tracking and therapeutic value of human adipose tissue-derived mesenchymal stem cell transplantation in reducing venous neointimal hyperplasia associated with arteriovenous fistula",
abstract = "Purpose: To determine if adventitial transplantation of human adipose tissue-derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1nu/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 (89Zr)-labeled MSCs serially with positron emission tomography (PET) for 21 days. Materials and Methods: All animal experiments were performed according to protocols approved by the institutional animal care and use committee. Fifty B6.Cg-Foxn1nu/J mice were used to accomplish the study aims. Green fluorescent protein was used to stably label 2.5 × 105 MSCs, which were injected into the adventitia of the outflow vein at the time of AVF creation in the MSC group. Eleven mice died after AVF placement. Animals were sacrificed on day 7 after AVF placement for real-time polymerase chain reaction (n = 6 for MSC and control groups) and histomorphometric (n = 6 for MSC and control groups) analyses and on day 21 for histomorphometric analysis only (n = 6 for MSC and control groups). In a separate group of experiments (n = 3), animals with transplanted 89Zrlabeled MSCs were serially imaged with PET for 3 weeks. Multiple comparisons were performed with two-way analysis of variance, followed by the Student t test with post hoc Bonferroni correction. Results: In vessels with transplanted MSCs compared with control vessels, there was a significant decrease in Mcp-1 gene expression (day 7: mean reduction, 62{\%}; P =.029), with a significant increase in the mean lumen vessel area (day 7: mean increase, 176{\%} [P =.013]; day 21: mean increase, 415{\%} [P =.011]). Moreover, this was accompanied by a significant decrease in Ki-67 index (proliferation on day 7: mean reduction, 81{\%} [P =.0003]; proliferation on day 21: mean reduction, 60{\%}, [P =.016]). Prolonged retention of MSCs at the adventitia was evidenced by serial PET images of 89Zr-labeled cells. Conclusion: Adventitial transplantation of MSCs decreases Mcp-1 gene expression, accompanied by a reduction in venous neointimal hyperplasia.",
author = "Binxia Yang and Akshaar Brahmbhatt and Torres, {Evelyn Nieves} and Brian Thielen and McCall, {Deborah L.} and Sean Engel and Aditya Bansal and Mukesh Pandey and Dietz, {Allan B} and Leof, {Edward B} and DeGrado, {Timothy R} and Debabrata Mukhopadhyay and Sanjay Misra",
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T1 - Tracking and therapeutic value of human adipose tissue-derived mesenchymal stem cell transplantation in reducing venous neointimal hyperplasia associated with arteriovenous fistula

AU - Yang, Binxia

AU - Brahmbhatt, Akshaar

AU - Torres, Evelyn Nieves

AU - Thielen, Brian

AU - McCall, Deborah L.

AU - Engel, Sean

AU - Bansal, Aditya

AU - Pandey, Mukesh

AU - Dietz, Allan B

AU - Leof, Edward B

AU - DeGrado, Timothy R

AU - Mukhopadhyay, Debabrata

AU - Misra, Sanjay

PY - 2016/5/1

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N2 - Purpose: To determine if adventitial transplantation of human adipose tissue-derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1nu/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 (89Zr)-labeled MSCs serially with positron emission tomography (PET) for 21 days. Materials and Methods: All animal experiments were performed according to protocols approved by the institutional animal care and use committee. Fifty B6.Cg-Foxn1nu/J mice were used to accomplish the study aims. Green fluorescent protein was used to stably label 2.5 × 105 MSCs, which were injected into the adventitia of the outflow vein at the time of AVF creation in the MSC group. Eleven mice died after AVF placement. Animals were sacrificed on day 7 after AVF placement for real-time polymerase chain reaction (n = 6 for MSC and control groups) and histomorphometric (n = 6 for MSC and control groups) analyses and on day 21 for histomorphometric analysis only (n = 6 for MSC and control groups). In a separate group of experiments (n = 3), animals with transplanted 89Zrlabeled MSCs were serially imaged with PET for 3 weeks. Multiple comparisons were performed with two-way analysis of variance, followed by the Student t test with post hoc Bonferroni correction. Results: In vessels with transplanted MSCs compared with control vessels, there was a significant decrease in Mcp-1 gene expression (day 7: mean reduction, 62%; P =.029), with a significant increase in the mean lumen vessel area (day 7: mean increase, 176% [P =.013]; day 21: mean increase, 415% [P =.011]). Moreover, this was accompanied by a significant decrease in Ki-67 index (proliferation on day 7: mean reduction, 81% [P =.0003]; proliferation on day 21: mean reduction, 60%, [P =.016]). Prolonged retention of MSCs at the adventitia was evidenced by serial PET images of 89Zr-labeled cells. Conclusion: Adventitial transplantation of MSCs decreases Mcp-1 gene expression, accompanied by a reduction in venous neointimal hyperplasia.

AB - Purpose: To determine if adventitial transplantation of human adipose tissue-derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1nu/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 (89Zr)-labeled MSCs serially with positron emission tomography (PET) for 21 days. Materials and Methods: All animal experiments were performed according to protocols approved by the institutional animal care and use committee. Fifty B6.Cg-Foxn1nu/J mice were used to accomplish the study aims. Green fluorescent protein was used to stably label 2.5 × 105 MSCs, which were injected into the adventitia of the outflow vein at the time of AVF creation in the MSC group. Eleven mice died after AVF placement. Animals were sacrificed on day 7 after AVF placement for real-time polymerase chain reaction (n = 6 for MSC and control groups) and histomorphometric (n = 6 for MSC and control groups) analyses and on day 21 for histomorphometric analysis only (n = 6 for MSC and control groups). In a separate group of experiments (n = 3), animals with transplanted 89Zrlabeled MSCs were serially imaged with PET for 3 weeks. Multiple comparisons were performed with two-way analysis of variance, followed by the Student t test with post hoc Bonferroni correction. Results: In vessels with transplanted MSCs compared with control vessels, there was a significant decrease in Mcp-1 gene expression (day 7: mean reduction, 62%; P =.029), with a significant increase in the mean lumen vessel area (day 7: mean increase, 176% [P =.013]; day 21: mean increase, 415% [P =.011]). Moreover, this was accompanied by a significant decrease in Ki-67 index (proliferation on day 7: mean reduction, 81% [P =.0003]; proliferation on day 21: mean reduction, 60%, [P =.016]). Prolonged retention of MSCs at the adventitia was evidenced by serial PET images of 89Zr-labeled cells. Conclusion: Adventitial transplantation of MSCs decreases Mcp-1 gene expression, accompanied by a reduction in venous neointimal hyperplasia.

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