The Current ‘State of Play’ of Regenerative Medicine in Horses: What the Horse Can Tell the Human

Smith, Roger K.; Garvican, Elaine R.; Fortier, Lisa A.

doi:10.2217/rme.14.42

Cited by 44 publications

(39 citation statements)

References 90 publications

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“…Equine tissues were used as the horse is the large model animal species in which most experiences exist regarding tendon pathophysiology [1] as well as MSC characteristics and MSC-based tendon therapies [36]. Furthermore, all experiments were performed with MSC from each of the 6 donor animals, without pooling the cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of Tenogenic Differentiation Mediated by Extracellular Tendon Matrix and Short‐Term Cyclic Stretching

Burk

Plenge

Brehm

et al. 2016

Stem Cells International

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Tendon and ligament pathologies are still a therapeutic challenge, due to the difficulty in restoring the complex extracellular matrix architecture and biomechanical strength. While progress is being made in cell-based therapies and tissue engineering approaches, comprehensive understanding of the fate of progenitor cells in tendon healing is still lacking. The aim of this study was to investigate the effect of decellularized tendon matrix and moderate cyclic stretching as natural stimuli which could potentially direct tenogenic fate. Equine adipose-derived mesenchymal stromal cells (MSC) were seeded on decellularized tendon matrix scaffolds. Mechanical stimulation was applied in a custom-made cyclic strain bioreactor. Assessment was performed 4 h, 8 h, and 24 h following mechanical stimulation. Scaffold culture induced cell alignment and changes in expression of tendon-related genes, although cell viability was decreased compared to monolayer culture. Short mechanical stimulation periods enhanced most of the scaffold-induced effects. Collagen 1A2 expression levels were decreased, while collagen 3A1 and decorin levels were increased. Tenascin-C and scleraxis expression showed an initial decrease but had increased 24 h after stimulation. The results obtained suggest that decellularized tendon matrix, supported by cyclic stretching, can induce tenogenic differentiation and the synthesis of tendon components important for matrix remodeling.

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Section: Discussionmentioning

confidence: 99%

Induction of Tenogenic Differentiation Mediated by Extracellular Tendon Matrix and Short‐Term Cyclic Stretching

Burk

Plenge

Brehm

et al. 2016

Stem Cells International

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“…Similar to humans, adipose tissue and bone marrow have been the MSC sources of choice in the horse, due to their relative ease of access and the number of putative stem cells they contain [2, 9–13]. Indeed, MSCs have been safely applied clinically to horses for well over a decade, now being an integral component of equine health care worldwide which has an estimated economic impact in the United States and the United Kingdom of $102 billion and $10 billion per annum, respectively.…”

Section: Introductionmentioning

confidence: 99%

Isolation and characterization of equine native MSC populations

et al. 2017

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BackgroundIn contrast to humans in which mesenchymal stem/stromal cell (MSC) therapies are still largely in the clinical trial phase, MSCs have been used therapeutically in horses for over 15 years, thus constituting a valuable preclinical model for humans. In human tissues, MSCs have been shown to originate from perivascular cells, namely pericytes and adventitial cells, which are identified by the presence of the cell surface markers CD146 and CD34, respectively. In contrast, the origin of MSCs in equine tissues has not been established, preventing the isolation and culture of defined cell populations in that species. Moreover, a comparison between perivascular CD146+ and CD34+ cell populations has not been performed in any species.MethodsImmunohistochemistry was used to identify adventitial cells (CD34+) and pericytes (CD146+) and to determine their localization in relation to MSCs in equine tissues. Isolation of CD34+ (CD34+/CD146–/CD144–/CD45–) and CD146+ (CD146+/CD34–/CD144–/CD45–) cell fractions from equine adipose tissue was achieved by fluorescence-activated cell sorting. The isolated cell fractions were cultured and analyzed for the expression of MSC markers, using qPCR and flow cytometry, and for the ability to undergo trilineage differentiation. Angiogenic properties were analyzed in vivo using a chorioallantoic membrane (CAM) assay.ResultsBoth CD34+ and CD146+ cells displayed typical MSC features, namely growth in uncoated tissue culture dishes, clonal growth when seeded at low density, expression of typical MSC markers, and multipotency shown by the capacity for trilineage differentiation. Of note, CD146+ cells were distinctly angiogenic compared with CD34+ and non-sorted cells (conventional MSCs), demonstrated by the induction of blood vessels in a CAM assay, expression of elevated levels of VEGFA and ANGPT1, and association with vascular networks in cocultures with endothelial cells, indicating that CD146+ cells maintain a pericyte phenotype in culture.ConclusionThis study reports for the first time the successful isolation and culture of CD146+ and CD34+ cell populations from equine tissues. Characterization of these cells evidenced their distinct properties and MSC-like phenotype, and identified CD146+ cells as distinctly angiogenic, which may provide a novel source for enhanced regenerative therapies.

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“…Several researches have been testing the immunogenicity of MSCs in horses and showing their safety in autologous and allogeneic transplants such as intradermal (5), intra-articular (9), intrathecal (10) and intralesional in tendon using BM and amniotic membrane cells (11). Additionally, equine is a good experimental model for extrapolating results to human medicine once it has several similarities to humans when referring to musculoskeletal diseases (12). Thus, this study tests the hypothesis that the intramuscular transplantation of UC-MSCs is safe for the equine experimental model with the possibility of extrapolating the results and benefits to other species, including human.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular Transplantation of Allogeneic Mesenchymal Stromal Cells Derived from Equine Umbilical Cord

Dias

Landim-Alvarenga

Moraes

et al. 2016

IJSC

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Background and ObjectivesMesenchymal stromal cells (MSCs) have great therapeutic potential, particularly in the process of tissue repair and immunomodulation through the secretion of biomolecules. Thus, the aim of this study was to evaluate the hypothesis that intramuscular transplantation of allogeneic MSCs obtained from equine umbilical cord (UC-MSCs) is safe, demonstrating that this is a suitable source of stem cells for therapeutic use.Methods and ResultsFor this, UC-MSCs were cultured, characterized and cryopreserved for future transplantation in six healthy mares. On day 0, transplantation of three million UC-MSCs diluted in Hank’s Balanced Solution (HBSS) was performed on right and left sides of the rump muscle. As a control, HBSS injections were performed caudally in the same muscle. Muscle biopsies were obtained as a control 30 days before transplantation (D-30). The biopsies were collected again on day 2 (left side) and day 7 (right side) post transplantation and examined histologically. All procedures were preceded by ultrasound examination and blood sampling. Hematologic evaluation remained within normal limits and no differences were observed between time points (p>0.05). Ultrasound examination was suggestive of inflammation 48 hours after transplantation in both groups (control and treated). At histological evaluation it was found only discrete inflammation signals between D-30×D2 (p<0.05) in the treated group, without differences (p> 0.05) between the groups at different time points.ConclusionsEquine UC-MSCs under the experimental conditions did not promote severe inflammation that causes tissue damage or lead to its rejection by the host organism and therefore has a good potential for clinical use.

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The Current ‘State of Play’ of Regenerative Medicine in Horses: What the Horse Can Tell the Human

Cited by 44 publications

References 90 publications

Induction of Tenogenic Differentiation Mediated by Extracellular Tendon Matrix and Short‐Term Cyclic Stretching

Induction of Tenogenic Differentiation Mediated by Extracellular Tendon Matrix and Short‐Term Cyclic Stretching

Isolation and characterization of equine native MSC populations

Intramuscular Transplantation of Allogeneic Mesenchymal Stromal Cells Derived from Equine Umbilical Cord

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