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Bioresorbable Mesenchymal Stem Cell–Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease

Allan John R. Barcena, Joy Vanessa D. Perez, Marvin Bernardino, Jossana A. Damasco, Andrea Cortes, Huckie Del Mundo, Erin Marie D. San Valentin, Carleigh Klusman, Gino Canlas, Francisco M. Heralde III, Rony Avritscher, Natalie Fowlkes, Jizhong Cheng, Steven Y. Huang, Marites P. Melancon
doi: https://doi.org/10.1101/2022.11.21.517369
Allan John R. Barcena
1Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, College of Medicine, University of the Philippines Manila, Manila 1000 Philippines
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Joy Vanessa D. Perez
2Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, College of Medicine, University of the Philippines Manila, Manila 1000 Philippines
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Marvin Bernardino
3Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Jossana A. Damasco
4Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Andrea Cortes
5Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Huckie Del Mundo
6Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Erin Marie D. San Valentin
7Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Carleigh Klusman
8Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, Baylor College of Medicine, Houston, TX 77030, USA
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Gino Canlas
9Department of Chemistry, Lamar University, 10009 Beaumont, TX 77710
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Francisco M. Heralde III
10College of Medicine, University of the Philippines Manila, Manila 1000 Philippines
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Rony Avritscher
11Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Natalie Fowlkes
12Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Jizhong Cheng
13Baylor College of Medicine, Houston, TX 77030, USA
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Steven Y. Huang
14Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Marites P. Melancon
15Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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  • For correspondence: mmelancon@mdanderson.org
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ABSTRACT

In the setting of chronic kidney disease (CKD), the periadventitial injection of mesenchymal stem cells (MSCs) has shown significant potential in improving arteriovenous fistula (AVF) maturation by inhibiting neointimal hyperplasia (NIH). However, the rapid clearance of MSCs remains a challenge. Hence, we fabricated an electrospun perivascular scaffold from polycaprolactone (PCL) to support MSC attachment and allow gradual MSC elution at the outflow vein, the AVF site most prone to NIH. We performed 5/6th nephrectomy to induce CKD in Sprague-Dawley rats, followed by direct AVF formation and perivascular scaffold application. We then compared the following groups of CKD rats: no perivascular scaffold (i.e., control), PCL scaffold, and PCL+MSC scaffold. On ultrasonography, the PCL and PCL+MSC groups showed significantly reduced wall thickness and wall-to-lumen ratio and increased luminal diameter and flow rate. Of note, PCL+MSC group showed greater improvement in luminal diameter and flow rate compared to PCL alone. Moreover, 18F-fluorodeoxyglucose positron emission tomography showed that only PCL+MSC resulted in a significant reduction in uptake. On histology, the PCL and PCL+MSC groups showed significantly reduced neointima-to-lumen and neointima-to- media ratios and reduced neointimal CD45, α-SMA, and vimentin fluorescence staining compared to control. Although the two scaffold treatments did not differ significantly in histology, in vivo imaging suggested that addition of MSCs promoted greater luminal expansion and blood flow and reduced the inflammatory process underlying NIH. Our results demonstrate the utility of a mechanical support loaded with MSCs at the outflow vein immediately after AVF formation to support maturation by minimizing NIH.

TRANSLATIONAL STATEMENT Current strategies to improve rates of arteriovenous fistula (AVF) maturation by minimizing neointimal hyperplasia (NIH) remain insufficient. Here, we pioneered a bioresorbable electrospun polymeric scaffold to deliver mesenchymal stem cells (MSCs) to the outflow vein, the site most prone to NIH in AVFs. This approach increased luminal diameter and flow rate and decreased inflammation and neointimal thickening, as seen on ultrasonography, 18F-FDG-PET, and histology. This study provides a foundation for the development and clinical use of MSC-seeded perivascular scaffolds that could improve AVF patency outcomes, reduce salvage interventions, and eventually reduce morbidity and mortality associated with vascular access failure.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵† Co-first authors

Copyright 
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Posted November 24, 2022.
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Bioresorbable Mesenchymal Stem Cell–Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease
Allan John R. Barcena, Joy Vanessa D. Perez, Marvin Bernardino, Jossana A. Damasco, Andrea Cortes, Huckie Del Mundo, Erin Marie D. San Valentin, Carleigh Klusman, Gino Canlas, Francisco M. Heralde III, Rony Avritscher, Natalie Fowlkes, Jizhong Cheng, Steven Y. Huang, Marites P. Melancon
bioRxiv 2022.11.21.517369; doi: https://doi.org/10.1101/2022.11.21.517369
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Bioresorbable Mesenchymal Stem Cell–Loaded Electrospun Polymeric Scaffold Inhibits Neointimal Hyperplasia Following Arteriovenous Fistula Formation in a Rat Model of Chronic Kidney Disease
Allan John R. Barcena, Joy Vanessa D. Perez, Marvin Bernardino, Jossana A. Damasco, Andrea Cortes, Huckie Del Mundo, Erin Marie D. San Valentin, Carleigh Klusman, Gino Canlas, Francisco M. Heralde III, Rony Avritscher, Natalie Fowlkes, Jizhong Cheng, Steven Y. Huang, Marites P. Melancon
bioRxiv 2022.11.21.517369; doi: https://doi.org/10.1101/2022.11.21.517369

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