The Archives of Bone and Joint Surgery

The Archives of Bone and Joint Surgery

Combination Effect of Rotator Cuff Repair with Secretome-hypoxia MSCs Ameliorates TNMD, RUNX2, and Healing Histology Score in Rotator Cuff Tear Rats

Document Type : RESEARCH PAPER

Authors
Meiky Fredianto 1
Herrry Herman 2
Yoyos Dias Ismiarto 3
Ambrosius Purba 4
Agung Putra 5
Nurul Hidayah 5
1 Doctoral Study Program, Faculty of Medicine, Padjadjaran University, Bandung, West Java, Indonesia
2 Division of Oncology, Department of Orthopedic Surgery, Faculty of Medicine, Padjadjaran University, Bandung, Indonesia
3 Department of Orthopedics and Traumatology, Faculty of Medicine, Padjadjaran University, Indonesia
4 Department of Physiology, Faculty of Medicine, Padjadjaran University, Bandung Indonesia
5 Stem Cell and Cancer Research, Semarang, Indonesia
10.22038/abjs.2023.67933.3218
Abstract
Objectives: In order to treat a rat model of rotator cuff rupture, this work concentrated on the expression 
of TNMD and RUNX2, followed by rotator cuff repair and secretome-hMSCs.
Methods: A total of thirty 10-weeks-old male Sprague–Dawley rats were separated into five groups randomly, RC 
on week 0, lesion treated with a rotator cuff repair and saline (RC + NaCl group, n = 6) for 2 and 8 weeks, and lesion 
treated with a rotator cuff repair and secretome-hMSCs (RC + secretome-hMSC group, n = 6) for 2 and 8 weeks. 
The supraspinatus and infraspinatus muscle–tendon units were obtained for histological and biomechanical 
investigation at 0, 2 and 8 weeks following injury.
Results: The findings showed that, in comparison with the RC + NaCl group, secretome-hMSCs significantly 
improved tendon repair by upregulating TNMD and RUNX2 expression and histology score.
Conclusion: Combining Secretome-hypoxia MSCs with RC healing may help rats with rotator cuff tears.
 Level of evidence: IV
Keywords
Mesenchymal stem cells
Rotator cuff tear
RUNX2
Secretome
TN MD
Subjects
  1. Sevivas N, Teixeira FG, Portugal R, et al. Mesenchymal Stem Cell Secretome Improves Tendon Cell Viability In Vitro and Tendon-Bone Healing In Vivo When a Tissue Engineering Strategy Is Used in a Rat Model of Chronic Massive Rotator Cuff Tear. Am J Sports Med. 2018; 46(2):449-459. doi: 10.1177/0363546517735850.
  2. Fu G, Lu L, Pan Z, Fan A, Yin F. Adipose-derived stem cell exosomes facilitate rotator cuff repair by mediating tendon-derived stem cells. Regen Med. 2021; 16(4):359-372. doi: 10.2217/RME-2021-0004.
  3. He J, Ping S, Yu F, Yuan X, Wang J, Qi J. Mesenchymal stem cell-derived exosomes: therapeutic implications for rotator cuff injury. Regen Med. 2021; 16(08):803-15. doi: 10.2217/rme-2020-0183.
  4. Xu T, Xu M, Bai J, et al. Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-β. Cytotechnology. 2019; 71(1):57-65. doi:10.1007/S10616-018-0264-Y/FIGURES/5.

5.                Saremi H, Amini M, Seifrabiei M. Comparison of Anterior and Posterior Transfer of Latissimus Dorsi Tendon to Humeral Head in Patients with Massive and Irreparable Rotator Cuff Tear. Arch Bone Jt Surg. 2023; 11(4):236-240. 

doi:10.22038/ABJS.2023.68222.3226.

  1. Cobb TE, Dimock RAC, Memon SD, et al. Rotator Cuff Repair With Patch Augmentation: What Do We Know? Arch Bone Jt Surg. 2022; 10(10):833-846. doi:10.22038/ABJS.2022.61345.3012.
  2. Stone MA, Henry TW, Gutman MJ, Ho JC, Namdari S, Orthopaedic R. Surgical Treatment of Shoulder Infection Following Rotator Cuff Repair. Arch Bone Jt Surg. 2023;11(2):111-116. doi:10.22038/ABJS.2022.52089.2572.
  3. Barry F. MSC Therapy for Osteoarthritis: An Unfinished Story. J Orthop Res. 2019; 37(6):1229-1235. doi:10.1002/JOR.24343.
  4. Lotfinia M, Lak S, Ghahhari NM, et al. Hypoxia pre-conditioned embryonic mesenchymal stem cell secretome reduces IL-10 production by peripheral blood mononuclear cells. Iran Biomed J. 2017; 21(1):24-31. doi:10.18869/acadpub.ibj.21.1.24.
  5. Putra A, Pertiwi D, Milla MN, et al. Hypoxia-preconditioned MSCs have superior effect in ameliorating renal function on acute renal failure animal model. Open Access Maced J Med Sci. 2019; 7(3):305-310. doi:10.3889/oamjms.2019.049.
  6. Putra A, Widyatmoko A, Ibrahim S, et al. Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia. F1000Res. 2021; 10:228. doi:10.12688/f1000research.51191.3.
  7. Rahimi B, Panahi M, Saraygord-Afshari N, et al. The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine. Mol Biol Rep. 2021;48(7):5607-5619. doi:10.1007/s11033-021-06360-7.
  8. Eleuteri S, Fierabracci A. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. Int J Mol Sci. 2019; 20(18):4597. doi: 10.3390/IJMS20184597.
  9. Yonemitsu R, Tokunaga T, Shukunami C, et al. Fibroblast Growth Factor 2 Enhances Tendon-to-Bone Healing in a Rat Rotator Cuff Repair of Chronic Tears. Am J Sports Med. 2019; 47(7):1701-1712. doi: 10.1177/0363546519836959.
  10. Valenti MT, Carbonare LD, Mottes M. Ectopic expression of the osteogenic master gene RUNX2 in melanoma. World J Stem Cells. 2018; 10(7):78. doi:10.4252/WJSC.V10.I7.78.
  11. Xia J, Minamino S, Kuwabara K, Arai S. Stem cell secretome as a new booster for regenerative medicine. Biosci Trends. 2019; 13(4):299-307. doi:10.5582/bst.2019.01226.

 

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  2. Wang C, Hu Q, Song W, Yu W, He Y. Adipose Stem Cell–Derived Exosomes Decrease Fatty Infiltration and Enhance Rotator Cuff Healing in a Rabbit Model of Chronic Tears. Am J Sports Med. 2020;48(6):1456-1464. doi: 10.1177/0363546520908847.
  3. Sevivas N, Teixeira FG, Portugal R, et al. Mesenchymal Stem Cell Secretome Improves Tendon Cell Viability In Vitro and Tendon-Bone Healing In Vivo When a Tissue Engineering Strategy Is Used in a Rat Model of Chronic Massive Rotator Cuff Tear. Am J Sports Med. 2018; 46(2):449-459. doi: 10.1177/0363546517735850.
  4. Zhen G, Wen C, Jia X, et al. Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis HHS Public Access. Nat Med. 2013; 19(6):704-712. doi:10.1038/nm.3143.
  5. Nugraha A, Putra A. Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats. Universa Med. 2018; 37(2):135. doi:10.18051/univmed.2018.v37.135-142.
  6. Sunarto H, Trisnadi S, Putra A, Sa’dyah NAC, Tjipta A, Chodidjah C. The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing. Indones J Cancer Chemoprevention. 2020; 11(3):134. doi: 10.14499/indonesianjcanchemoprev11iss3pp134-143.
  7. Hamra NF, Putra A, Tjipta A, Amalina ND, Nasihun T. Hypoxia mesenchymal stem cells accelerate wound closure improvement by controlling α-smooth muscle actin expression in the full-thickness animal model. Open Access Maced J Med Sci. 2021; 9:35-41. doi:10.3889/oamjms.2021.5537.
  8. Putra A, Rosdiana I, Darlan DM, et al. Intravenous Administration is the Best Route of Mesenchymal Stem Cells Migration in Improving Liver Function Enzyme of Acute Liver Failure. Folia Med (Plovdiv). 2020; 62(1):52-58. doi:10.3897/folmed.62.e47712.
  9. Grogan SP, Barbero A, Winkelmann V, et al. Visual histological grading system for the evaluation of in vitro-generated neocartilage. Tissue Eng. 2006; 12(8):2141-2149. doi:10.1089/ten.2006.12.2141.
  10. Ren Y, Zhang S, Wang Y, et al. Effects of purified exosome product on rotator cuff tendon-bone healing in vitro and in vivo. Biomaterials. 2021; 276:121019. doi:10.1016/J.BIOMATERIALS.2021.121019.
  11. Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The pi3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019 30; 68(Suppl 2):S131-S138. doi:10.33549/PHYSIOLRES.934345.
  12. Gunawardena TNA, Rahman MT, Abdullah BJJ, Kasim NHA. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J Tissue Eng Regen Med. 2019; 13(4):569-586. doi:10.1002/TERM.2806.
  13. Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci. 2020; 21(19):1-15. doi: 10.3390/ijms21197038.
  14. Bari E, Ferrarotti I, Saracino L, et al. Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae? Cells. 2021; 10(5):1203. doi: 10.3390/CELLS10051203.

31.              Rahimi B, Panahi M, Saraygord-Afshari N, et al. The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine. Mol Biol Reports. 2021; 48(7):5607-5619. doi: 10.1007/S11033-021-

  1. Sevivas N, Teixeira FG, Portugal R, et al. Mesenchymal Stem Cell Secretome Improves Tendon Cell Viability In Vitro and Tendon-Bone Healing In Vivo When a Tissue Engineering Strategy Is Used in a Rat Model of Chronic Massive Rotator Cuff Tear. Am J Sports Med. 2018; 46(2):449-459. doi: 10.1177/0363546517735850.
  2. Fu G, Lu L, Pan Z, Fan A, Yin F. Adipose-derived stem cell exosomes facilitate rotator cuff repair by mediating tendon-derived stem cells. Regen Med. 2021; 16(4):359-372. doi: 10.2217/RME-2021-0004.
  3. He J, Ping S, Yu F, Yuan X, Wang J, Qi J. Mesenchymal stem cell-derived exosomes: therapeutic implications for rotator cuff injury. Regen Med. 2021; 16(08):803-15. doi: 10.2217/rme-2020-0183.
  4. Xu T, Xu M, Bai J, et al. Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-β. Cytotechnology. 2019; 71(1):57-65. doi:10.1007/S10616-018-0264-Y/FIGURES/5.
  5. Saremi H, Amini M, Seifrabiei M. Comparison of Anterior and Posterior Transfer of Latissimus Dorsi Tendon to Humeral Head in Patients with Massive and Irreparable Rotator Cuff Tear. Arch Bone Jt Surg. 2023; 11(4):236-240. doi:10.22038/ABJS.2023.68222.3226.
  6. Cobb TE, Dimock RAC, Memon SD, et al. Rotator Cuff Repair With Patch Augmentation: What Do We Know? Arch Bone Jt Surg. 2022; 10(10):833-846. doi:10.22038/ABJS.2022.61345.3012.
  7. Stone MA, Henry TW, Gutman MJ, Ho JC, Namdari S, Orthopaedic R. Surgical Treatment of Shoulder Infection Following Rotator Cuff Repair. Arch Bone Jt Surg. 2023;11(2):111-116. doi:10.22038/ABJS.2022.52089.2572.
  8. Barry F. MSC Therapy for Osteoarthritis: An Unfinished Story. J Orthop Res. 2019; 37(6):1229-1235. doi:10.1002/JOR.24343.
  9. Lotfinia M, Lak S, Ghahhari NM, et al. Hypoxia pre-conditioned embryonic mesenchymal stem cell secretome reduces IL-10 production by peripheral blood mononuclear cells. Iran Biomed J. 2017; 21(1):24-31. doi:10.18869/acadpub.ibj.21.1.24.
  10. Putra A, Pertiwi D, Milla MN, et al. Hypoxia-preconditioned MSCs have superior effect in ameliorating renal function on acute renal failure animal model. Open Access Maced J Med Sci. 2019; 7(3):305-310. doi:10.3889/oamjms.2019.049.
  11. Putra A, Widyatmoko A, Ibrahim S, et al. Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia. F1000Res. 2021; 10:228. doi:10.12688/f1000research.51191.3.
  12. Rahimi B, Panahi M, Saraygord-Afshari N, et al. The secretome of mesenchymal stem cells and oxidative stress: challenges and opportunities in cell-free regenerative medicine. Mol Biol Rep. 2021;48(7):5607-5619. doi:10.1007/s11033-021-06360-7.
  13. Eleuteri S, Fierabracci A. Insights into the Secretome of Mesenchymal Stem Cells and Its Potential Applications. Int J Mol Sci. 2019; 20(18):4597. doi: 10.3390/IJMS20184597.
  14. Yonemitsu R, Tokunaga T, Shukunami C, et al. Fibroblast Growth Factor 2 Enhances Tendon-to-Bone Healing in a Rat Rotator Cuff Repair of Chronic Tears. Am J Sports Med. 2019; 47(7):1701-1712. doi: 10.1177/0363546519836959.
  15. Valenti MT, Carbonare LD, Mottes M. Ectopic expression of the osteogenic master gene RUNX2 in melanoma. World J Stem Cells. 2018; 10(7):78. doi:10.4252/WJSC.V10.I7.78.
  16. Xia J, Minamino S, Kuwabara K, Arai S. Stem cell secretome as a new booster for regenerative medicine. Biosci Trends. 2019; 13(4):299-307. doi:10.5582/bst.2019.01226.

 

  1. Yustianingsih V, Sumarawati T, Putra A. Hypoxia enhances self-renewal properties and markers of mesenchymal stem cells. Universa Medicina. 2019; 38(3):164-71. doi:10.18051/UnivMed.2019.v38.164-171.
  2. Wang C, Hu Q, Song W, Yu W, He Y. Adipose Stem Cell–Derived Exosomes Decrease Fatty Infiltration and Enhance Rotator Cuff Healing in a Rabbit Model of Chronic Tears. Am J Sports Med. 2020;48(6):1456-1464. doi: 10.1177/0363546520908847.
  3. Sevivas N, Teixeira FG, Portugal R, et al. Mesenchymal Stem Cell Secretome Improves Tendon Cell Viability In Vitro and Tendon-Bone Healing In Vivo When a Tissue Engineering Strategy Is Used in a Rat Model of Chronic Massive Rotator Cuff Tear. Am J Sports Med. 2018; 46(2):449-459. doi: 10.1177/0363546517735850.
  4. Zhen G, Wen C, Jia X, et al. Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis HHS Public Access. Nat Med. 2013; 19(6):704-712. doi:10.1038/nm.3143.
  5. Nugraha A, Putra A. Tumor necrosis factor-α-activated mesenchymal stem cells accelerate wound healing through vascular endothelial growth factor regulation in rats. Universa Med. 2018; 37(2):135. doi:10.18051/univmed.2018.v37.135-142.
  6. Sunarto H, Trisnadi S, Putra A, Sa’dyah NAC, Tjipta A, Chodidjah C. The Role of Hypoxic Mesenchymal Stem Cells Conditioned Medium in Increasing Vascular Endothelial Growth Factors (VEGF) Levels and Collagen Synthesis to Accelerate Wound Healing. Indones J Cancer Chemoprevention. 2020; 11(3):134. doi: 10.14499/indonesianjcanchemoprev11iss3pp134-143.
  7. Hamra NF, Putra A, Tjipta A, Amalina ND, Nasihun T. Hypoxia mesenchymal stem cells accelerate wound closure improvement by controlling α-smooth muscle actin expression in the full-thickness animal model. Open Access Maced J Med Sci. 2021; 9:35-41. doi:10.3889/oamjms.2021.5537.
  8. Putra A, Rosdiana I, Darlan DM, et al. Intravenous Administration is the Best Route of Mesenchymal Stem Cells Migration in Improving Liver Function Enzyme of Acute Liver Failure. Folia Med (Plovdiv). 2020; 62(1):52-58. doi:10.3897/folmed.62.e47712.
  9. Grogan SP, Barbero A, Winkelmann V, et al. Visual histological grading system for the evaluation of in vitro-generated neocartilage. Tissue Eng. 2006; 12(8):2141-2149. doi:10.1089/ten.2006.12.2141.
  10. Ren Y, Zhang S, Wang Y, et al. Effects of purified exosome product on rotator cuff tendon-bone healing in vitro and in vivo. Biomaterials. 2021; 276:121019. doi:10.1016/J.BIOMATERIALS.2021.121019.
  11. Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J. The pi3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res. 2019 30; 68(Suppl 2):S131-S138. doi:10.33549/PHYSIOLRES.934345.
  12. Gunawardena TNA, Rahman MT, Abdullah BJJ, Kasim NHA. Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine. J Tissue Eng Regen Med. 2019; 13(4):569-586. doi:10.1002/TERM.2806.
  13. Ahangar P, Mills SJ, Cowin AJ. Mesenchymal stem cell secretome as an emerging cell-free alternative for improving wound repair. Int J Mol Sci. 2020; 21(19):1-15. doi: 10.3390/ijms21197038.
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The Archives of Bone and Joint Surgery
Volume 11, Issue 10
October 2023
Pages 617-624

  • Receive Date 17 March 2023
  • Revise Date 27 July 2023
  • Accept Date 20 July 2023