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Table 1 Summary of in vivo studies of cell therapy for tendon injury in horse

From: Strategies of tenogenic differentiation of equine stem cells for tendon repair: current status and challenges

Cell source and injected cell number

Supplement

Follow-up

Evaluation

Observation

Pros/cons

Reference

BM-MSCs

5 × 106 in 1 ml

–

3 years

Comparison with 2 large study with the same follow-up but treated in other ways for 141 horses with natural model injury (overstrain)

No side effects; reduction of the re-injury rate

Long-term efficacy of MSCs/not include the contralateral limb

[16]

BM-MSC

10 × 106 in 2 ml

BM supernatant

3 months

Comparison of the effect of supernatant alone or with cell on collagen fibril size and tensile strength (surgical model)

No difference in collagen fibril diameter and strength between control injury and treated injury

The surgical model for tendon injury induces standardized traumatic fiber damage/the surgical model does not represent certain aspects of natural injury

[17]

ADNC

–

6 weeks

Short-term efficacy of ADNC fractions for 8 horses with collagenase-induced tendinitis

Improved tendon organization and COMP expression in treated tendons

Cons: long-term studies are needed

[15]

ASCs

10 × 106 in 0.5 ml

–

120 days

Effect of cell therapy for 8 horses with collagenase-induced tendonitis

No adverse effects; minimal cellularity; parallel arranged extracellular matrix similar to normal tendon; greater collagen deposits compared with the control group

Cons: long-term studies are needed, and biomechanical and genetic expression analyses are needed

[18]

ASCs

10 × 106 in 1 ml

PC

16 weeks

Effect of AD-MSCs combined with PC for therapy of 8 horses with collagenase-induced tendonitis

Greater organization; decreased inflammation; increased blood flow; no difference in the expression of the SCX, TNMD., COL 1 and 3, and TNC between the control and treatment groups

Double centrifugation for the collection of the PC/non-activated PC

[19]

ASCs

1 × 106 in 5–10 ml

PRP

9 months

Effect of single injection of cells in 9 athletic horses with spontaneous and acute lameness of SDFT

Decrease in the size of the lesion after 60 days; full alignment of tendon fibers after 120 days; seven horses resumed their normal competitive activity after 7 or 9 months; two horses had relapsed

Pros: rehabilitation program after cell therapy

[20]

Allogeneic ASCs

2 × 106 in 1 ml

PRP

24 weeks

Safety and efficacy of a therapy of 19 horses with acute (less than 10 days old) or sub-acute (less than 20 days old) overstrain SDFT injury

No immune response existed; 89.5% of the horses returned to their previous competing level

Rehabilitation program/no control group was included; higher number of animals; histological, biochemical, and biomechanical data is required

[21]

ASCs

10 × 106 in 2 ml

(1.5 ml injected)

–

Up to 9 weeks

Potential low-field MRI to monitor the fate of cells labeled with SPIO nanoparticles (surgical model tendinopathy)

High numbers of cells were present in lesion site

Small number of horses were included; controlled clinical trials are needed; monitoring for a longer time is needed

[22]

Labeled ASCs

10 × 106 in 1 ml

Serum

24 weeks

Long-term cell tracking of MSC after local application into tendon lesions and its effect on tendon healing (surgical procedure with collagenase application)

Part of cells appeared to remain viable and integrated within the injured tissue; no difference between MSC-treated tendons and the serum-injected controls at 24 weeks

MRI is an advantageous for long-term tracking/MRI is not suitable for systemic distribution of labeled cells; SPIO-induced hypointense artifacts. Exact percentage of cells surviving is needed

[23, 24]

Allogeneic UCB-MSCs

2–10 × 106 in ml

 

6 months

Therapeutic effect of repeated injection UCB-MSCs on tendon and ligament of 52 horses; natural core lesion/anechogenic diffuse lesion

77% (40 horses) regained their higher level of performance

Cons: lack of a sufficient control group

[25]

oAECs

7 × 106 in 0.5 ml

–

18 months, 180 days

Efficacy of healing process in fifteen horses with acute tendon lesions; efficacy of regeneration in acute and chronic lesion

Any adverse reaction to oAEC xenotransplantation and 12 horses resumed competition and their previous activity after 18 months; outcome was similar in both acute and chronic lesions after 180 days

Long-term follow-up/optimal number of injected cells and higher number of chronic cases is required

[26, 27]

BM-MSC and ESC

1 × 106 in 0.5 ml

–

3 months

Monitor survival of injected cells into lesion (surgical model)

BM-MSC survival was less than 5% after 10 days; ESC numbers were at a constant level for 90 days in the absence of tumorigenesis

Two different labels which are used to detect the 2 cell types; not able to compare their detection efficiencies due to different sensitivities

[28]

MSC and IGF -I gene-enhanced MSC

10 × 106 in 1 ml

–

8 weeks

Evaluated for biochemical composition and mechanical test; collagenase-induced lesions

No different effect between both of cells

Cons: optimal dose of MSCs, extended IGF-I expression and less viral vectors for IGF-I delivery should be investigated

[29]

Tenogenic induction allogeneic Pb-MSCs

2–3 × 106 in 1 ml

PRP

2 years

Safety and clinical efficacy for 6 week; long-term efficacy of a combination of PRP and MSCs to treat natural tendon injury

No adverse effect; no calcification; low re-injury rate after 2 years (18% vs 44%)

Cons: no control groups were included; veterinary practitioners for scoring were not blinded

[30, 31]

TSPCs

5 × 106 in 0.15 ml at 2 sites (1 × 107 cells in total)

–

16 weeks

Evaluate the efficacy of autogenous TSPC injections in a collagenase-induced model injury

Improved the tensile strength and collagen fiber alignment

Cons: long-term effect of TDPCs on the biomechanical properties will be determined

[32]

  1. Abbreviations: BM-MSCs bone marrow-derived mesenchymal stem cells, ASCs adipose tissue-derived MSCs, ESCs embryonic stem-like cells, ADNC adipose-derived nucleated cell, TSPCs tendon-derived progenitor cells, PC platelet concentrate, Pb-MSCs peripheral blood-derived mesenchymal stem cells, oAECs ovine amniotic epithelial cells, COMP cartilage oligomeric matrix protein, COL3 collagen type III, COL1 collagen type I, TNMD tenomodulin, TNC tenascin-C