The Superior Healing Capacity of MRL Tendons is Minimally Influenced by the Systemic Environment of the MRL Mouse

Overview

Journal Sci Rep

Specialty Science

Date 2023 Oct 11

PMID 37821476

Authors

Borys Frankewycz

Rebecca Bell

Monideepa Chatterjee

Nelly Andarawis-Puri

Affiliations

Soon will be listed here.

Abstract

Murphy Roths Large mice (MRL) exhibit improved tendon healing and are often described as a "super-healer" strain. The underlying mechanisms that drive the superior healing response of MRL remain a controversial subject. We utilized a tendon transplantation model between MRL and "normal-healer" B6-mice to differentiate between the contribution of MRL's innate tendon and systemic environment to its improved healing capacity. Patellar tendons with a midsubstance punch injury were transplanted back into the same animal (autograft) or into an animal of the other strain (allograft). Findings at 4 weeks showed that the innate MRL tendon environment drives its improved healing capacity as demonstrated by improved stiffness and maximum load in MRL-grafts-in-B6-host-allografts compared to B6-autografts, and higher modulus in MRL-autografts compared to B6-graft-in-MRL-host-allografts. Groups with an MRL component showed an increase in pro-inflammatory cytokines in the 3 days after injury, suggesting an early enhanced inflammatory profile in MRL that ultimately resolves. A preserved range of motion of the knee joint in all MRL animals suggests a systemic "shielding effect" of MRL in regard to joint adhesiveness. Our findings 4-weeks post injury are consistent with previous studies showing tissue-driven improved healing and suggest that the systemic environment contributes to the overall healing process.

References

Connizzo B, Yannascoli S, Tucker J, Caro A, Riggin C, Mauck R . The detrimental effects of systemic Ibuprofen delivery on tendon healing are time-dependent. Clin Orthop Relat Res. 2013; 472(8):2433-9. PMC: 4079885. DOI: 10.1007/s11999-013-3258-2. View

Schneider M, Angele P, Jarvinen T, Docheva D . Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing. Adv Drug Deliv Rev. 2017; 129:352-375. DOI: 10.1016/j.addr.2017.12.016. View

Lin T, Cardenas L, Soslowsky L . Biomechanics of tendon injury and repair. J Biomech. 2004; 37(6):865-77. DOI: 10.1016/j.jbiomech.2003.11.005. View

Fitzgerald J, Rich C, Burkhardt D, Allen J, Herzka A, Little C . Evidence for articular cartilage regeneration in MRL/MpJ mice. Osteoarthritis Cartilage. 2008; 16(11):1319-26. DOI: 10.1016/j.joca.2008.03.014. View

Paredes J, Pekmezian A, Andarawis-Puri N . MRL/MpJ tendon matrix-derived therapeutic promotes improved healing outcomes in scar-mediated canonical tendon healing. J Orthop Res. 2020; 39(7):1548-1560. PMC: 7680300. DOI: 10.1002/jor.24754. View

Hopkins C, Fu S, Chua E, Hu X, Rolf C, Mattila V . Critical review on the socio-economic impact of tendinopathy. Asia Pac J Sports Med Arthrosc Rehabil Technol. 2017; 4:9-20. PMC: 5730665. DOI: 10.1016/j.asmart.2016.01.002. View

Tucker B, Klassen H, Yang L, Chen D, Young M . Elevated MMP Expression in the MRL Mouse Retina Creates a Permissive Environment for Retinal Regeneration. Invest Ophthalmol Vis Sci. 2008; 49(4):1686-95. PMC: 2613950. DOI: 10.1167/iovs.07-1058. View

Lewis Jr J, Furman B, Zeitler E, Huebner J, Kraus V, Guilak F . Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice. Arthritis Rheum. 2012; 65(3):660-70. PMC: 3721663. DOI: 10.1002/art.37796. View

Wang R, Jiang W, Zhang L, Xie S, Zhang S, Yuan S . Intra-articular delivery of extracellular vesicles secreted by chondrogenic progenitor cells from MRL/MpJ superhealer mice enhances articular cartilage repair in a mouse injury model. Stem Cell Res Ther. 2020; 11(1):93. PMC: 7052980. DOI: 10.1186/s13287-020-01594-x. View

10.

Abdullah I, Lepore J, Epstein J, Parmacek M, Gruber P . MRL mice fail to heal the heart in response to ischemia-reperfusion injury. Wound Repair Regen. 2005; 13(2):205-8. DOI: 10.1111/j.1067-1927.2005.130212.x. View

11.

Gourevitch D, Kossenkov A, Zhang Y, Clark L, Chang C, Showe L . Inflammation and Its Correlates in Regenerative Wound Healing: An Alternate Perspective. Adv Wound Care (New Rochelle). 2014; 3(9):592-603. PMC: 4152783. DOI: 10.1089/wound.2014.0528. View

12.

Heber-Katz E, Leferovich J, Bedelbaeva K, Gourevitch D, Clark L . The scarless heart and the MRL mouse. Philos Trans R Soc Lond B Biol Sci. 2004; 359(1445):785-93. PMC: 1693365. DOI: 10.1098/rstb.2004.1468. View

13.

Morita W, Snelling S, Wheway K, Watkins B, Appleton L, Carr A . ERK1/2 drives IL-1β-induced expression of TGF-β1 and BMP-2 in torn tendons. Sci Rep. 2019; 9(1):19005. PMC: 6908634. DOI: 10.1038/s41598-019-55387-1. View

14.

Christensen L, Arnesen C, Moller S, Hyldig N . The effect of compression therapy on post-surgical swelling and pain after total knee arthroplasty. Int J Orthop Trauma Nurs. 2020; 41:100815. DOI: 10.1016/j.ijotn.2020.100815. View

15.

Lantto I, Heikkinen J, Flinkkila T, Ohtonen P, Leppilahti J . Epidemiology of Achilles tendon ruptures: increasing incidence over a 33-year period. Scand J Med Sci Sports. 2014; 25(1):e133-8. DOI: 10.1111/sms.12253. View

16.

Kovacevic D, Rodeo S . Biological augmentation of rotator cuff tendon repair. Clin Orthop Relat Res. 2008; 466(3):622-33. PMC: 2505220. DOI: 10.1007/s11999-007-0112-4. View

17.

Sun H, Schaniel C, Leong D, Wang J . Biology and mechano-response of tendon cells: Progress overview and perspectives. J Orthop Res. 2015; 33(6):785-92. PMC: 4422159. DOI: 10.1002/jor.22885. View

18.

Frankewycz B, Cimino D, Andarawis-Puri N . Murine patellar tendon transplantation requires transosseous cerclage augmentation - development of a transplantation model for investigation of systemic and local drivers to healing. J Orthop Surg Res. 2019; 14(1):410. PMC: 6889740. DOI: 10.1186/s13018-019-1475-4. View

19.

George N, Bell R, Paredes J, Taub P, Andarawis-Puri N . Superior mechanical recovery in male and female MRL/MpJ tendons is associated with a unique genetic profile. J Orthop Res. 2020; 39(6):1344-1354. PMC: 7606617. DOI: 10.1002/jor.24705. View

20.

Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang X, Leferovich J . Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc Natl Acad Sci U S A. 2010; 107(13):5845-50. PMC: 2851923. DOI: 10.1073/pnas.1000830107. View