Cellular and Humoral Immunogenicity Investigation of Single and Repeated Allogeneic Tenogenic Primed Mesenchymal Stem Cell Treatments in Horses Suffering From Tendon Injuries

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Abstract

The use of mesenchymal stem cells (MSCs) for the treatment of equine tendon disease is widely investigated because of their regenerative and immunomodulatory potential. However, questions have been raised concerning the immunogenic properties of allogeneic MSCs. Therefore, two studies were conducted to assess the safety of equine allogeneic peripheral blood-derived tenogenic primed MSCs (tpMSCs). The objective was to evaluate if a single and repeated tpMSC administration induced a cellular and humoral immune response in horses suffering from tendon injuries. Horses enrolled in the first study ( n = 8) had a surgically induced superficial digital flexor tendon core lesion and were treated intralesionally with tpMSCs. Before and after treatment the cellular immunogenicity was assessed by modified mixed lymphocyte reactions. The humoral immune response was investigated using a crossmatch assay. Presence of anti-bovine serum albumin (BSA) antibodies was detected via ELISA. Horses enrolled in the second study ( n = 6) suffered from a naturally occurring tendon injury and were treated twice with tpMSCs. Blood was collected after the second treatment for the same immunological assays. No cellular immune response was found in any of the horses. One out of eight horses in the first study and none of the horses in the second study had anti-tpMSC antibodies. This particular horse had an equine sarcoid and further investigation revealed presence of antibodies against sarcoid cells and epithelial-like stem cells before treatment, which increased after treatment. Additionally, formation of antibodies against BSA was observed. These findings might indicate a non-specific immune response generated after treatment. Serum from the other horses revealed no such antibody formation. These two studies showed that the administration of tpMSCs did not induce a cellular or humoral immune response following an intralesional single or repeated (two consecutive) allogeneic tpMSC treatment in horses with tendon injury, except for one horse. Therefore, a larger field study should confirm these findings and support the safe use of tpMSCs as a therapeutic for horses suffering from tendon injuries.

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Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

M Dominici, K Le Blanc, I. Mueller … (2006)

The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.

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Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model

Amanda-Jo Joswig, Alexis Mitchell, Kevin J Cummings … (2017)

Background Intra-articular injection of mesenchymal stem cells (MSCs) is efficacious in osteoarthritis therapy. A direct comparison of the response of the synovial joint to intra-articular injection of autologous versus allogeneic MSCs has not been performed. The objective of this study was to assess the clinical response to repeated intra-articular injection of allogeneic versus autologous MSCs prepared in a way to minimize xeno-contaminants in a large animal model. Methods Intra-articular injections of bone marrow-derived, culture-expanded MSCs to a forelimb metacarpophalangeal joint were performed at week 0 and week 4 (six autologous; six autologous with xeno-contamination; six allogeneic). In the week following each injection, clinical and synovial cytology evaluations were performed. Results Following the first intra-articular injection, there were no differences in clinical parameters over time. Following the second intra-articular injection, there was a significant adverse response of the joint to allogeneic MSCs and autologous MSCs with xeno-contamination with elevated synovial total nucleated cell counts. There was also significantly increased pain from joints injected with autologous MSCs with xeno-contamination. Conclusions Repeated intra-articular injection of allogeneic MSCs results in an adverse clinical response, suggesting there is immune recognition of allogeneic MSCs upon a second exposure. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0503-8) contains supplementary material, which is available to authorized users.

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Mesenchymal stem cells used for rabbit tendon repair can form ectopic bone and express alkaline phosphatase activity in constructs.

G. Boivin, Mark Harris, Aodhán Butler … (2004)

Mesenchymal stem cells (MSCs) have been used to repair connective tissue defects in several animal models. Compared to "natural healing" controls (no added cells), MSC-collagen gel constructs in rabbit tendon defects significantly improve repair biomechanics. However, ectopic bone forms in 28% of MSC-treated rabbit tendons. To understand the source of bone formation, three studies were performed. In the first study, the hypothesis was tested that MSCs delivered during surgery contribute to bone formation in the in vivo repair site. Adjacent histological sections in the MSC-treated repair tissue were examined for pre-labeled MSCs and for cells showing positive alkaline phosphatase (ALP) activity. Both cells were observed in serial sections in regions of ectopic bone. Contralateral "natural healing" tendons lacked both markers. In the other two studies, the effects of osteogenic supplements and construct geometry (monolayer vs. 3-D) on ALP activity were studied to test three hypotheses: that rabbit MSCs increase ALP activity over time in monolayer culture conditions; that adding osteogenic inducing supplements to the culture medium increases cellular protein in monolayer culture; and that rabbit MSCs increase ALP activity both in monolayer and in 3-D constructs, with and without media supplements. Culture in monolayer under similar conditions to in vivo (as in the first study) did not increase ALP at 2 or 4 weeks. Medium designed to increase osteogenic activity significantly increased cell numbers (cellular protein increased by 260%) but did not affect ALP activity either in monolayer or 3-D constructs (p>0.12). However, MSCs in 3-D constructs exhibited higher ALP activity than cells in monolayer, both in the presence (p<0.045) and absence of supplement (p<0.005). These results suggest that in vitro conditions may critically influence cell differentiation and protein expression. Mechanisms responsible for these effects are currently under investigation.

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Author and article information

Contributors

Eva Depuydt: URI : http://loop.frontiersin.org/people/886554/overview

Koen Chiers: URI : http://loop.frontiersin.org/people/729763/overview

Marco Patruno: URI : http://loop.frontiersin.org/people/232257/overview

Laura Da Dalt: URI : http://loop.frontiersin.org/people/916319/overview

Luc Duchateau: URI : http://loop.frontiersin.org/people/710311/overview

Jimmy Saunders: URI : http://loop.frontiersin.org/people/1321063/overview

Ann Martens: URI : http://loop.frontiersin.org/people/1064746/overview

Lore Van Hecke: URI : http://loop.frontiersin.org/people/1220325/overview

Jan H. Spaas: URI : http://loop.frontiersin.org/people/78057/overview

Journal

Journal ID (nlm-ta): Front Vet Sci

Journal ID (iso-abbrev): Front Vet Sci

Journal ID (publisher-id): Front. Vet. Sci.

Title: Frontiers in Veterinary Science

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2297-1769

Publication date (Electronic): 24 February 2022

Publication date Collection: 2021

Volume: 8

Electronic Location Identifier: 789293

Affiliations

[1] ¹Boehringer Ingelheim Veterinary Medicine Belgium , Evergem, Belgium

[2] ²Department of Surgery and Anaesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University , Merelbeke, Belgium

[3] ³Department of Pathology, Bacteriology and Poultry Diseases, Faculty of Veterinary Medicine, Ghent University , Merelbeke, Belgium

[4] ⁴Department of Comparative Biomedicine and Food Science (BCA), University of Padova , Padova, Italy

[5] ⁵Biometrics Research Group, Faculty of Veterinary Medicine, Ghent University , Merelbeke, Belgium

[6] ⁶Department of Veterinary Medical Imaging and Small Animal Orthopaedics, Faculty of Veterinary Medicine, Ghent University , Merelbeke, Belgium

Author notes

Edited by: Chavaunne T. Thorpe, Royal Veterinary College (RVC), United Kingdom

Reviewed by: Laura Barrachina, Universidad de Zaragoza, Spain; Barbara Merlo, University of Bologna, Italy

*Correspondence: Eva Depuydt Eva.Depuydt@ 123456Boehringer-Ingelheim.com

This article was submitted to Veterinary Regenerative Medicine, a section of the journal Frontiers in Veterinary Science

Article

DOI: 10.3389/fvets.2021.789293

PMC ID: 8907452

PubMed ID: 35281431

SO-VID: 3b068a4b-1925-43a4-be7c-961f952b84b1

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 04 October 2021

Date accepted : 31 December 2021

Page count

Figures: 4, Tables: 2, Equations: 0, References: 58, Pages: 11, Words: 8093

Funding

Funded by: Agentschap Innoveren en Ondernemen, doi 10.13039/100012331;

Funded by: Boehringer Ingelheim, doi 10.13039/100001003;

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Cellular and Humoral Immunogenicity Investigation of Single and Repeated Allogeneic Tenogenic Primed Mesenchymal Stem Cell Treatments in Horses Suffering From Tendon Injuries

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Most cited references 58

Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model

Mesenchymal stem cells used for rabbit tendon repair can form ectopic bone and express alkaline phosphatase activity in constructs.

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