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MRL/MpJ tendon matrix-derived therapeutic promotes improved healing outcomes in scar-mediated canonical tendon healing.

ABSTRACT: Tendons are commonly injured connective soft tissues characterized by an ineffective healing response that results in scar formation and loss of functional and structural properties. Naturally occurring extracellular matrix (ECM) constructs have become a promising therapeutic for tendon injuries due to their capacity to harness a complex biological environment. However, in tendon, the ECM properties needed for improved healing remain unknown. Interestingly, we have determined that the improved tendon healing response of the scarless-healing MRL/MpJ is driven by intrinsic properties with therapeutic potential to modulate the proliferative and morphological behavior of cells derived from a canonically healing model in vitro. We hypothesize that a distinct composition of ECM deposited during the early healing response of the MRL/MpJ will harnesses the biological cues to stimulate improved structure and function in vivo of canonically healing B6 mice. Accordingly, MRL/MpJ and B6 patellar tendons were injured via midsubstance punch defects. Healing tendons were isolated after 3 or 7 days and encapsulated in PEG-4MAL hydrogels to develop ECM-derived therapeutic constructs. Constructs were then introduced into B6 mice as a treatment following full thickness midsubstance-punch injuries. Treatment with ECM-derived constructs from MRL/MpJ tendons after 7-days post-injury (M7) resulted in improved matrix alignment, tissue stiffness, decreased collagen III content and improved cell morphology in B6 tendons after 6 weeks post-injury. Furthermore, proteomic analysis showed that M7 contained a unique compositional profile rich in glycoproteins, thereby elucidating a valuable naturally-derived platform for the treatment of tendon injuries. Overall this work highlights promising targets for future therapeutic development and tissue engineering applications.

SUBMITTER: Paredes J

PROVIDER: S-EPMC7680300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveAdult elastic cartilage has limited repair capacity. MRL/MpJ (MRL) mice, by contrast, are capable of spontaneously healing ear punctures. This study was undertaken to characterize microbiome differences between healer and non-healer mice and to evaluate whether this healing phenotype can be transferred via gut microbiome transplantation.MethodsWe orally transplanted C57BL/6J (B6) mice with MRL/MpJ cecal contents at weaning and as adults (n = 57) and measured ear hole closure 4 weeks after a 2.0mm punch and compared to vehicle-transplanted MRL and B6 (n = 25) and B6-transplanted MRL (n = 20) mice. Sex effects, timing of transplant relative to earpunch, and transgenerational heritability were evaluated. In a subset (n = 58), cecal microbiomes were profiled by 16S sequencing and compared to ear hole closure. Microbial metagenomes were imputed using PICRUSt.ResultsTransplantation of B6 mice with MRL microbiota, either in weanlings or adults, improved ear hole closure. B6-vehicle mice healed ear hole punches poorly (0.25±0.03mm, mm ear hole healing 4 weeks after a 2mm ear hole punch [2.0mm-final ear hole size], mean±SEM), whereas MRL-vehicle mice healed well (1.4±0.1mm). MRL-transplanted B6 mice healed roughly three times as well as B6-vehicle mice, and half as well as MRL-vehicle mice (0.74±0.05mm, P = 6.9E-10 vs. B6-vehicle, P = 5.2E-12 vs. MRL-vehicle). Transplantation of MRL mice with B6 cecal material did not reduce MRL healing (B6-transplanted MRL 1.3±0.1 vs. MRL-vehicle 1.4±0.1, p = 0.36). Transplantation prior to ear punch was associated with the greatest ear hole closure. Offspring of transplanted mice healed significantly better than non-transplanted control mice (offspring:0.63±0.03mm, mean±SEM vs. B6-vehicle control:0.25±0.03mm, n = 39 offspring, P = 4.6E-11). Several microbiome clades were correlated with healing, including Firmicutes (R = 0.84, P = 8.0E-7), Lactobacillales (R = 0.65, P = 1.1E-3), and Verrucomicrobia (R = -0.80, P = 9.2E-6). Females of all groups tended to heal better than males (B6-vehicle P = 0.059, MRL-transplanted B6 P = 0.096, offspring of MRL-transplanted B6 P = 0.0038, B6-transplanted MRL P = 1.6E-6, MRL-vehicle P = 0.0031). Many clades characteristic of female mouse cecal microbiota vs. males were the same as clades characteristic of MRL and MRL-transplanted B6 mice vs. B6 controls, including including increases in Clostridia and reductions in Verrucomicrobia in female mice.ConclusionIn this study, we found an association between the microbiome and tissue regeneration in MRL mice and demonstrate that this trait can be transferred to non-healer mice via microbiome transplantation. We identified several microbiome clades associated with healing.

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MRL/MpJ tendon matrix-derived therapeutic promotes improved healing outcomes in scar-mediated canonical tendon healing.

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