Combined ascorbic acid and T 3  produce better healing compared to bone marrow mesenchymal stem cells in an Achilles tendon injury rat model: a proof of concept study

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Abstract

Background

This pilot study aimed to ascertain whether the local application of ascorbic acid (AA), of T ₃, and of rat (r) bone marrow mesenchymal stem cells (BMSCs), alone or in all possible combinations, promoted healing after an Achilles tendon injury in a rat model.

Methods

An Achilles tendon defect was produced in 24 6–8-week-old male inbred Lewis rats. The animals were then randomly divided into eight groups of three rats each. The tendon defect was filled with 50 μL of phosphate-buffered saline (PBS) containing (1) 50 μg/mL AA (AA group), (2) 10 ⁻⁷ M T ₃ (T ₃ group), (3) 4 × 10 ⁶ rBMSCs (rBMSC group), (4) 50 μg/mL AA + 10 ⁻⁷ M T ₃ (AA + T ₃ group), (5) 4 × 10 ⁶ rBMSCs + 50 μg/mL AA (rBMSC + AA group), (6) 4 × 10 ⁶ rBMSCs + 10 ⁻⁷ M T ₃ (rBMSC + T ₃ group), (7) 4 × 10 ⁶ rBMSCS + 50 μg/mL AA + 10 ⁻⁷ M T ₃ (rBMSC + AA + T ₃ group), and (8) PBS only (control group: CTRL). All treatments were administered by local injection immediately after the tendons had been damaged; additionally, AA was injected also on the second and fourth day from the first injection (for groups 1, 4, 5, and 7), and T ₃ was injected again every day for 4 days (for groups 2, 4, 6, and 7). At 30 days from initial treatment, tendon samples were harvested, and the quality of tendon repair was evaluated using histological and histomorphological analysis. The structure and morphology of the injured Achilles tendons were evaluated using the modified Svensson, Soslowsky, and Cook score, and the collagen type I and III ratio was calculated.

Results

The group treated with AA combined with T ₃ displayed the lowest Svensson, Soslowsky, and Cook total score value of all tissue sections at histopathological examination, with fiber structure close to regular orientation, normal-like tendon vasculature, and no cartilage formation. AA + T ₃ also showed the highest collagen I and the lowest collagen III values compared to all other treatments including the CTRL.

Conclusion

There are potential benefits using a combination of AA and T ₃ to accelerate tendon healing.

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Most cited references 40

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Biology of tendon injury: healing, modeling and remodeling.

P. Sharma, N Maffulli (2006)

Tendon disorders are frequent, and are responsible for much morbidity both in sport and the workplace. Although the presence of degenerative changes does not always lead to symptoms, pre-existing degeneration has been implicated as a risk factor for acute tendon rupture. The term tendinopathy is a generic descriptor of the clinical conditions in and around tendons arising from overuse. The terms "tendinosis" and "tendinitis/tendonitis" should only be used after histopathological examination. Disordered healing is seen in tendinopathy, and inflammation is not typically seen. In acute injuries, the process of tendon healing is an indivisible process that can be categorized into three overlapping phases for descriptive purposes. Tendon healing can occur intrinsically, via proliferation of epitenon and endotenon tenocytes, or extrinsically, by invasion of cells from the surrounding sheath and synovium. Despite remodeling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. Tendon injuries account for considerable morbidity, and often prove disabling for several months, despite what is considered appropriate management. Chronic problems caused by overuse of tendons probably account for 30% of all running-related injuries, and the prevalence of elbow tendinopathy in tennis players can be as high as 40%. The basic cell biology of tendons is still not fully understood, and the management of tendon injury poses a considerable challenge for clinicians. This article describes the structure of tendons, and reviews the pathophysiology of tendon injury and healing.

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Types and epidemiology of tendinopathy.

L Almekinders, Nicola Maffulli, Louis C Almekinders (2003)

During the last few decades, the role of sports and physical activity has become more and more important in all modern communities. The risk of tendon injury has thus increased, and prevention has become important. Epidemiologic studies are important when planning prevention programs for tendon injuries. Because of individual sport cultures and different sport habits in different countries, national epidemiologic studies are of importance in each individual country.

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Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

Ting-Ting Zhang, Wayne Lee, Yun-Feng Rui … (2013)

Introduction Mesenchymal stem cells (MSCs) are known to migrate to tumor tissues. This behavior of MSCs has been exploited as a tumor-targeting strategy for cell-based cancer therapy. However, the effects of MSCs on tumor growth are controversial. This study was designed to determine the effect of MSCs on the growth of breast and prostate tumors. Methods Bone marrow-derived MSCs (BM-MSCs) were isolated and characterized. Effects of BM-MSCs on tumor cell proliferation were analyzed in a co-culture system with mouse breast cancer cell 4T1 or human prostate cancer cell DU145. Tumor cells were injected into nude mice subcutaneously either alone or coupled with BM-MSCs. The expression of cell proliferation and angiogenesis-related proteins in tumor tissues were immunofluorescence analyzed. The angiogenic effect of BM-MSCs was detected using a tube formation assay. The effects of the crosstalk between tumor cells and BM-MSCs on expression of angiogenesis related markers were examined by immunofluorescence and real-time PCR. Results Both co-culturing with mice BM-MSCs (mBM-MSCs) and treatment with mBM-MSC-conditioned medium enhanced the growth of 4T1 cells. Co-injection of 4T1 cells and mBM-MSCs into nude mice led to increased tumor size compared with injection of 4T1 cells alone. Similar experiments using DU145 cells and human BM-MSCs (hBM-MSCs) instead of 4T1 cells and mBM-MSCs obtained consistent results. Compared with tumors induced by injection of tumor cells alone, the blood vessel area was greater in tumors from co-injection of tumor cells with BM-MSCs, which correlated with decreased central tumor necrosis and increased tumor cell proliferation. Furthermore, both conditioned medium from hBM-MSCs alone and co-cultures of hBM-MSCs with DU145 cells were able to promote tube formation ability of human umbilical vein endothelial cells. When hBM-MSCs are exposed to the DU145 cell environment, the expression of markers associated with neovascularization (macrophage inflammatory protein-2, vascular endothelial growth factor, transforming growth factor-beta and IL-6) was increased. Conclusion These results indicate that BM-MSCs promote tumor growth and suggest that the crosstalk between tumor cells and BM-MSCs increased the expression of pro-angiogenic factors, which may have induced tumor cell proliferation and angiogenesis thereby increasing solid tumor growth.

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Author and article information

Contributors

Francesco Oliva: olivafrancesco@hotmail.it

Nicola Maffulli:

ORCID: http://orcid.org/0000-0002-5327-3702

n.maffulli@qmul.ac.uk

Clarissa Gissi: gissi.clarissa@libero.it

Francesca Veronesi: francesca.veronesi@ior.it

Lucia Calciano: lucia.calciano@univr.it

Milena Fini: milena.fini@ior.it

Silvia Brogini: silvia.brogini@ior.it

Marialucia Gallorini: marialuciagallorini@gmail.com

Cristina Antonetti Lamorgese Passeri: cristinaalp94@gmail.com

Roberta Bernardini: roberta.bernardini@uniroma2.it

Rosella Cicconi: rosella.cicconi@uniroma2.it

Maurizio Mattei: mattei@uniroma2.it

Anna Concetta Berardi: annacberardi@yahoo.it

Journal

Journal ID (nlm-ta): J Orthop Surg Res

Journal ID (iso-abbrev): J Orthop Surg Res

Title: Journal of Orthopaedic Surgery and Research

Publisher: BioMed Central (London )

ISSN (Electronic): 1749-799X

Publication date (Electronic): 18 February 2019

Publication date PMC-release: 18 February 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 54

Affiliations

[1 ]GRID grid.459369.4, Department of Orthopaedics and Traumatology, Surgery and Dentistry, , Azienda Ospedaliera San Giovanni di Dio e Ruggi d’Aragona, University of Salerno School of Medicine, ; Salerno, Italy

[2 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Centre for Sports and Exercise Medicine, , Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Mile End Hospital, ; London, UK

[3 ]Institute of Science and Technology in Medicine, Keele University Medical School, Stoke on Trent, UK

[4 ]GRID grid.461844.b, U.O.C. of Immunohaematology and Transfusion Medicine, Laboratory of Stem Cells, , Spirito Santo Hospital, ; Pescara, Italy

[5 ]ISNI 0000 0001 2154 6641, GRID grid.419038.7, Laboratory of Preclinical and Surgical Studies, Research Innovation and Technology Department (RIT), , IRCCS Rizzoli Orthopedic Institute, ; Via di Barbiano 1/10, 40136 Bologna, Italy

[6 ]ISNI 0000 0004 1763 1124, GRID grid.5611.3, Dipartimento di Sanità Pubblica e Medicina di Comunità, Sezione di Epidemiologia e Statistica Medica, , Università di Verona, ; 37134 Verona, Italy

[7 ]ISNI 0000 0001 2181 4941, GRID grid.412451.7, Department of Medical, Oral and Biotechnological Sciences, , University “G. d’Annunzio” Chieti-Pescara, ; Chieti, Italy

[8 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Interdepartmental Service Centre - Station for Animal Technology, , University of Rome “Tor Vergata”, ; Rome, Italy

[9 ]ISNI 0000 0001 2300 0941, GRID grid.6530.0, Department of Biology, , University of Rome “Tor Vergata”, ; Rome, Italy

Author information

Nicola Maffulli http://orcid.org/0000-0002-5327-3702

Article

Publisher ID: 1098

DOI: 10.1186/s13018-019-1098-9

PMC ID: 6380036

PubMed ID: 30777116

SO-VID: dfc7fafc-be4d-416b-942d-39e4d63f6b3a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 June 2018

Date accepted : 7 February 2019

Funding

Funded by: PCFF Foundation, Pescara, Italy

Award ID: PCFF-2017-27.3

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ScienceOpen disciplines: Surgery

Keywords: ascorbic acid,thyroid hormones,t3, bone marrow mesenchymal stem cells,tendon

Data availability:

ScienceOpen disciplines: Surgery

Keywords: ascorbic acid, thyroid hormones, t3, bone marrow mesenchymal stem cells, tendon

Combined ascorbic acid and T ₃ produce better healing compared to bone marrow mesenchymal stem cells in an Achilles tendon injury rat model: a proof of concept study

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Most cited references 40

Biology of tendon injury: healing, modeling and remodeling.

Types and epidemiology of tendinopathy.

Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors

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