Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier?
Abstract
:1. Introduction
2. Mesenchymal Stromal Cells and Veterinary Regenerative Medicine: Main Features, Sources, Isolation, and Cryopreservation Procedures
2.1. MSC Isolation Tissue
2.2. MSC Isolation Procedures
2.3. MSC Culturing Conditions
2.4. Cryopreservation
2.5. Quality Controls
2.6. Routes for MSC Administration
2.7. Autologous vs Allogeneic MSCs
3. MSCs in the Veterinary Field: Disease Targets
3.1. Osteoarthritis
3.2. Tendon Ligament Injury
3.3. Intervertebral Disk Degeneration
4. Animal Spontaneous Pathologies as Potential Preclinical Models for Human Therapy
5. Secretome and Extracellular Vesicles as a Potential Therapy for Different Disease Areas
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | Animal | Study Design | Time | Outcome | Dosage |
---|---|---|---|---|---|
Carrade et al. [51] | Horses | Autologous vs Allogeneic placenta-derived MSCs | 0–72 h post-injection | Allogeneic MSCs did not provoke a systemic response, and the minimal inflammatory reaction was found to be similar to the autologous effect | 7.5 × 106 in 2 mL sterile injectable 0.9% NaCl |
Shah et al. [52] | Dogs | Allogeneic adipose tissue (AD)-MSC | 10 weeks | Better quality of life also demonstrating the safety of the allogeneic treatment | Data not recorded |
Guest et al. [53] | Horses | Autologous and Allogeneic progenitor cells (MPCs) purified from bone marrow And bone marrow supernatant alone | 10 or 34 days | Post-mortem examinations showed no visible cell-mediated immune response to allogeneic MPCs in any of the treated horses | 1 × 106 cells suspended in 0.5 mL of autologous bone marrow supernatant |
Brandão et al. [54] | Horses | Autologous and allogeneic AD-MSCs and only PBS as a control group | 6 days | All groups presented mild pain sensitivity, there were no significant differences among the groups in the physical, morphological, thermography, and ultrasonography analyses. Also, the lameness analysis presented similar behaviour between the two cell-treated groups. Both allogeneic and autologous AD-MSCs did not induce a significant inflammatory response, although a higher number of T lymphocytes have been found in the allogeneic treatment. | 1 × 107 cells for each application resuspended in PBS. |
Disease | Animal | Treatment | Route and Dosage | Outcome | Ref. |
---|---|---|---|---|---|
AO- hip | Dog (n = 8) | Autologous AD-MSCs in combination with plasma rich in growth factor (PRGF-Endoret) | Intra-articular injection of over 30 × 106 AD-MSC | Reduced of lameness and absence of side effects for all the period (six months). | [64] |
AO- hip | Dogs (n = 15) | Autologous AD-MSCs alone | Intra-articular injection of over 30 × 106 AD-MSC | Reduced of lameness only in the first month (less than three months). | [65] |
AO- hip | Dogs (n = 39) | Comparison between AD-MSCs versus PRGF | Intra-articular injection of 30 × 106 AD-MSC | Dog’s pain was reduced, physical function was improved, and no side effects were found. AD-MSC showed better results in the period considered (six months). | [67] |
AO- hip (coxofemoral joints) | Dogs (n = 4) | Autologous AD-MSCs in phosphate-buffered saline (PBS) | Dogs received intra-articular injection of either suspension of 4.2–5 × 106 (depending on cell yield) AD-MSCs in 0.6 mL PBSor only 0.6 mL of PBS as a control group | Significant improvement in lameness compared to the control group in the considered period (three months). | [68] |
AO- humeroradial (elbow) joints | Dogs (n = 14) | Autologous AD-MSCs in phosphate-buffered saline (PBS) | Dogs received an intra-articular injection of 3–5 × 106 (depending on cell yield) AD-MSC in 0.6 mL PBS | Significant improvement in lameness, range of motion, and pain on manipulation over time (six months). | [69] |
OA-stifle injury (femoral condyles) | Horses (n = 10) | Autologous bone marrow (BM)-MSCs in hyaluronan (HA) | Intra-articular injection of either 20 × 106 BMSCs with 22 mg of HA or 22 mg of HA alone | In the period of 12 months: no evidence of clinically significant improvement but arthroscopic evaluation confirmed a significant increase in tissue repair. Immunohistochemical analysis demonstrated more aggrecan levels in the repaired tissue treated with BM-MSC. | [71] |
OA | Horses (n = 16) | Comparison between autologous AD-MSC versus steroid drugs (Betamethasone) | Intra-articular injection of 3 groups: (1): 1 mL of AD-MSC in normal saline, at a concentration of 5 × 106 cells/mL (2): 1 mL of betamethasone (3): control untreated | No change in lameness at 30 days but reduced at 60 days. At the period of 180 days, improvement remained in AD-MSC group but not in the steroid group. In the control group, the level of lameness did not change. | [74] |
OA- degenerated stifle, fetlock, pastern and coffin joints | Horses (n = 165) In detail: stifle (n = 30), fetlock (n = 58), pastern (n = 34) and coffin (n = 43) joints | Allogenic peripheral blood MSCs with or without chondrogenic induction in combination with PRP | Intra-articular injection. Dosage not stated | Considering 180 weeks period: no adverse effects were noticed, except for three patients. Already after six weeks, 45% (native MSCs) and 60% (chondrogenic-induced MSCs) of the treated patients returned to normality, and the beneficial effects further increased after 18 weeks (78% for native MSCs and 86% for chondrogenic induced MSCs). | [41] |
OA-stifle injury (femorotibial lesions (meniscal, cartilage or ligamentous) | Horses (n = 33) | Autologous BM-MSCs post-surgery (arthroscopy) | Intra-articular injection of 15–20 × 106 BM-MSC in autologous serum/5% DMSO + HA compared to surgery alone | Considering 24 months of follow up: Improvements in ability were realised with BMSC treatment compared to surgery alone. | [72] |
OA- degenerative fetlock joint disease | Horses (n = 75) | Allogeneic chondrogenic induced MSCs added to allogeneic plasma (EAP) | Intra-articular injection of 2 × 106 allogeneic chondrogenic induced MSCs with EAP | After long-term follow-up (one year), horses were returned to their previous level of work. | [75] |
Disease | Animal | Treatment | Route and Dosage | Outcome | Ref. |
---|---|---|---|---|---|
TLI- superficial digital flexor tendon (SDFT) | Horses (n = 8) | AD-MSC suspended in platelet concentrate (PC) | Intralesional administration of 10 × 106 AD-MSC in in 1 mL of PC. 1 mL of PBS was used as a control group | After 16 weeks improvements were reported for AD-MSC group. In detail: decrease of the lesion progression and inflammatory reaction, better organization of collagen fibres, an increase of blood flow. No difference in terms of gene expression was found. | [80] |
TLI- SDFT | Horses (n = 141, racehorses) | BM-MSC resuspended in their bone marrow supernatant | Intralesional BM-MSC injection was performed resuspending cells in their bone marrow supernatant at the concentration of 5 × 106 cells/mL. | Two years follow up: no side effects; the need for reinjury was lower than other published works. | [84] |
TLI | Horses (n = 6) | Allogeneic AD-MSCs | Injection of 100 × 106 allogeneic AD-MSCs via atlanto-occipital (AO) and lumbosacral (LS) injection | AD-MSCs administration was safe. No alterations in blood and neurological examinations at any time (30 days) either with AO or LS injections. OA had better distribution. | [86] |
TLI | Horses (n = 10) | Allogeneic AD-MSC compared with BM-MSC | Intravenous injections of three doses of 25 × 106 allogeneic AD-MSC and BM-MSC respectively | After the first injection, horses were followed up for 35 days. Evaluation was made on the inflammatory and immune response showing that repeated BM-MSC injection increased blood CD8+ T-cell numbers. | [85] |
TLI- SDFT (forelimbs) | Horses (n = 12) | Comparison between autologous AD-MSC, BM-MSC, and platelet-rich plasma (PRP) | Injury injections of 20 × 106 BM-MSCs or AD-MSCs suspended in 7 mL of lactated Ringer’s solution (LRS), and 7 mL of PRP. 7mL of LRS was used as control | After 45 weeks, all treatments had beneficial effects, but in detail, data suggest BM-MSCs might be the better approach for tendon healing. | [88] |
TLI- suspensory ligament (SL)or superficial digital flexor tendon (SDFT) lesion | Horses (SL n = 68) (SDFT n = 36) | Tenogenically induced allogeneic peripheral blood (PB)MSCs combined with PRP | intralesional injection of 1ml of PB-derived MSCs (containing 2-–3 × 106) with 1 mL of PRP | In two years, no adverse effects have been observed. At 12 weeks, results were convincing in lesions improvement where about 80% of both SL and SDFT groups went back to their previous performance. | [87] |
TLI-SDFT | Horses (n = 11) | Autologous BM-MSC | Injections of at least 1 × 106 of BM-MSCs were re-suspended in 1.5 mL of autologous serum | Patients were back to their sports activities, without having suffered a re-injury | [91] |
TLI- SDFT | Horses (n = 12) | Autologous BM-MSC suspended in 2 mL of BM supernatant | Implantation of 10 × 106 BM-MSCs were suspended in 2 mL of citrated BM supernatant. 2 mL of PBS were used as a control group | In six months, there were significant benefits in terms of safety and healing tendon process (reduced stiffness, histological showed better organization and reduction in re-injury rate). | [81] |
TLI- supraspinatus tendinopathy | Dogs (n = 41) | BM-MSCs in combination with PRP | Ultrasound-guided intratendineous injection of BM-MSCs with PRP (1:1 ratio) | On 90 days post-treatment: in most cases, the fibre pattern and echogenicity have improved, while only a minority resolved fibre pattern and echogenicity abnormalities. | [96] |
TLI- partial cranial cruciate ligament tear | Dogs (n = 36) 19 cases received BM-MSC while 17 cases received AD-MSC | Autologous BM-MSCs vs AD-MSCs were combined with platelet-rich plasma (PRP) in 1:1 ratio when injected. | 2–4 mL of BM-MSCs + PRP or 1–2 mL of AD-MSCs + PRP was injected intra-articularly into the stifle (volume depended on the dog’s size) | Neither treatment was superior to the other in terms of outcome (90 days). | [94] |
Disease | Animal | Treatment | Route and dosage | Outcome | Ref. |
---|---|---|---|---|---|
IVDD | Dogs (n = 6) | Autologous BM-MSCs | Intradiscal injection of 2 × 106 BM-MSCs suspended in 1 mL 10% autologous plasma in PBS. Only PSB solution was used for group control | Twelve months after treatment: even if the injection was well tolerated with no side effects, no successful treatment was found in any dogs. | [98] |
IVDD- lumbosacral | Dogs (n = 20) | Autologous BM-MSCs | Intradiscal injection of 3 × 106 was applied in three different groups—(1) intradiscal injection of MSC-microcarriers (n = 11), (2) MSC-TGF-β1-microcarriers (n = 6), and (3) microcarriers only during a decompressing spinal surgery (n = 3) | Ten months after treatment: injection was successful in all dogs; thus, they returned to normality. Schmorl’s nodes were found as side effects. | [99] |
IVDD-chronic spinal cord injury | Dogs (n = 7) | Allogeneic foetal BM-MSCs | Intramedullary injection of 1 × 106 allogeneic BM-MSCs | Ninety days evaluation showed no side effects, increased movement of the hind limbs, and increased locomotory function. | [100] |
IVDD- Thoracolumbar intervertebral disc disease | Dogs (n = 34) | Allogeneic AD-MSCs + surgery | Intraoperative intraspinal allogeneic AD-MSCs of 1 × 107 cells | Six months after treatment: Improvement in the neurological exam and better endpoint with AD-MSCs application rather than surgery only. | [101] |
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Mocchi, M.; Dotti, S.; Del Bue, M.; Villa, R.; Bari, E.; Perteghella, S.; Torre, M.L.; Grolli, S. Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier? Cells 2020, 9, 1453. https://doi.org/10.3390/cells9061453
Mocchi M, Dotti S, Del Bue M, Villa R, Bari E, Perteghella S, Torre ML, Grolli S. Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier? Cells. 2020; 9(6):1453. https://doi.org/10.3390/cells9061453
Chicago/Turabian StyleMocchi, Michela, Silvia Dotti, Maurizio Del Bue, Riccardo Villa, Elia Bari, Sara Perteghella, Maria Luisa Torre, and Stefano Grolli. 2020. "Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier?" Cells 9, no. 6: 1453. https://doi.org/10.3390/cells9061453
APA StyleMocchi, M., Dotti, S., Del Bue, M., Villa, R., Bari, E., Perteghella, S., Torre, M. L., & Grolli, S. (2020). Veterinary Regenerative Medicine for Musculoskeletal Disorders: Can Mesenchymal Stem/Stromal Cells and Their Secretome Be the New Frontier? Cells, 9(6), 1453. https://doi.org/10.3390/cells9061453