Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium

Abstract

BackgroundIntra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs.MethodsA lesion was made in the lateral border of the lateral branch of the ovine deep digital flexor tendon within the digital sheath and 2 weeks later 5 million autologous bone marrow MSCs were injected under ultrasound guidance into the digital sheath. Tendons were recovered post mortem at 1 day, and 1–2, 4, 12 and 24 weeks after MSC injection. For the 1-day and 1–2-week groups, MSCs labelled with fluorescent-conjugated magnetic iron-oxide nanoparticles (MIONs) were tracked with MRI, histology and flow cytometry. The 4, 12 and 24-week groups were implanted with non-labelled cells and compared with saline-injected controls for healing.ResultsThe MSCs displayed no reduced viability in vitro to an uptake of 20.0 ± 4.6 pg MIONs per cell, which was detectable by MRI at minimal density of ~ 3 × 104 cells. Treated limbs indicated cellular distribution throughout the tendon synovial sheath but restricted to the synovial tissues, with no MSCs detected in the tendon or surgical lesion.The lesion was associated with negligible morbidity with minimal inflammation post surgery. Evaluation of both treated and control lesions showed no evidence of healing of the lesion at 4, 12 and 24 weeks on gross and histological examination.ConclusionsUnlike other laboratory animal models of tendon injury, this novel model mimics the failed tendon healing seen clinically intra-synovially. Importantly, however, implanted stem cells exhibited homing to synovium niches where they survived for at least 14 days. This phenomenon could be utilised in the development of novel physical or biological approaches to enhance localisation of cells in augmenting intra-synovial tendon repair.

Evaluation of the Effects of Synovial Multipotent Cells on Deep Digital Flexor Tendon Repair in a Large Animal Model of Intra‐Synovial Tendinopathy

“…The SMCs recovered from normal tendon sheath synovium were found to be a heterogeneous population of cells exhibiting differences in proliferation, clonogenicity, multipotentiality, and cell‐surface marker expression. While displaying an overall spindle‐like fibroblastic morphology similar to bone marrow‐derived MSCs, SMCs yielded substantially lower number of CFUs compared with percentages commonly reported for bone marrow MSCs . The highly variable population doubling times of SMCs also contrasted with that reported for bone marrow MSCs (106.8 ± 99.2 and 32.29 ± 1.72 h, respectively) .…”

“…Accurate placement was identified by the presence of echogenic air bubbles present inside the sheath cavity post‐injection. The control group has been previously reported, which showed no healing for vehicle‐only (PBS without cells) injected into this sheep tendon injury model …”

“…Random cell samples ( n = 7) were selected for an assessment of tri‐lineage differentiation and evaluated as previously described for bone marrow‐derived MSCs …”

“…We hypothesized that implanted cells could either seal the defect from the synovial environment and/or participate in regenerative tissue repair. However, autologous bone marrow MSC implantation does not augment intra‐synovial tendon repair where these cells only engraft and persist within synovial tissue …”

“…SMCs carry an advantage, in that they are easily retrievable from the tendon sheath synovium for use in homologous fashion (reimplantation into same location from where originally retrieved). Therefore, we hypothesized that tissue specificity of synovial MSCs with the intra‐synovial micro‐environment would enable an improved healing response compared with the ineffectiveness of bone marrow MSCs …”