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Combined effect of ligament stem cells and umbilical-cord-blood-derived CD34+ cells on ligament healing

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Abstract

Transplantation of ligament-tissue-derived stem cells has become a promising approach in the repair of injured ligament. Neovascularization plays an important role in ligament healing and remodeling. Recently, human umbilical-cord-blood-derived CD34+ cells have been reported to contribute to neoangiogenesis. Therefore, we performed a series of experiments to test our hypothesis that the combination of medial collateral ligament stem cells (MCL-SCs) and umbilical-cord-blood-derived CD34+ cells has synergistic effects on tendon healing. MCL-SCs and umbilical-cord-blood-derived CD34+ cells were isolated and cultured. Rat MCL injury was treated by MCL-SCs and/or CD34+ cells. Response to the cell therapy was assessed by gross observation, histological evaluation and biomechanical testing at 2 and 4 weeks after each treatment. Although each cell therapy group induced macroscopic and morphological recovery in healing MCLs, the combined use of MCL-SCs/CD34+ cells led to further improvement in healing quality. Capillary density was significantly higher in the CD34+ cell transplantation groups than in the other groups at week 2. Biomechanical testing demonstrated that the failure load of the healing ligament was greatest in the combination therapy group. The combination of MCL-SCs and CD34+ cells as a cell therapeutic thus enhances healing and restores biomechanical function toward normal after MCL injury. The findings obtained in our study suggest that the combination of MCL-SCs and CD34+ cells transplantation represents a promising strategy for ligament injury.

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References

  • Bi Y, Ehirchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13:1219–1227

    Article  CAS  PubMed  Google Scholar 

  • Bonaros N, Rauf R, Wolf D, Margreiter E, Tzankov A, Schlechta B, Kocher A, Ott H, Schachner T, Hering S, Bonatti J, Laufer G (2006) Combined transplantation of skeletal myoblasts and angiopoietic progenitor cells reduces infarct size and apoptosis and improves cardiac function in chronic ischemic heart failure. J Thorac Cardiovasc Surg 132:1321–1328

    Article  PubMed  Google Scholar 

  • Chen L, Dong SW, Liu JP, Tao X, Tang KL, Xu JZ (2012) Synergy of tendon stem cells and platelet-rich plasma in tendon healing. J Orthop Res 30:991–997

    Article  CAS  PubMed  Google Scholar 

  • Chen SH, Wang JJ, Chen CH, Chang HK, Lin MT, Chang FM, Chio CC (2014) Umbilical cord blood-derived CD34+ cells improve outcomes of traumatic brain injury in rats by stimulating angiogenesis and neurogenesis. Cell Transplant 23:959–979

    Article  PubMed  Google Scholar 

  • Fukui N, Katsuragawa Y, Sakai H, Oda H, Nakamura K (1998) Effect of local application of basic fibroblast growth factor on ligament healing in rabbits. Rev Rhum Engl Ed 65:406–414

    CAS  PubMed  Google Scholar 

  • Gnecchi M, Zhang Z, Ni A, Dzau VJ (2008) Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 103:1204–1219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW (2012) Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308:2369–2379

    Article  CAS  PubMed  Google Scholar 

  • Janowska-Wieczorek A, Majka M, Ratajczak J, Ratajczak MZ (2001) Autocrine/paracrine mechanisms in human hematopoiesis. Stem Cells 19:99–107

    Article  CAS  PubMed  Google Scholar 

  • Kanaya A, Deie M, Adachi N, Nishimori M, Yanada S, Ochi M (2007) Intra-articular injection of mesenchymal stromal cells in partially torn anterior cruciate ligaments in a rat model. Arthroscopy 23:610–617

    Article  PubMed  Google Scholar 

  • Kao CH, Chen SH, Chio CC, Lin MT (2008) Human umbilical cord blood-derived CD34+ cells may attenuate spinal cord injury by stimulating vascular endothelial and neurotrophic factors. Shock 29:49–55

    PubMed  Google Scholar 

  • Liang R, Woo SL, Nguyen TD, Liu PC, Almarza A (2008) Effects of a bioscaffold on collagen fibrillogenesis in healing medial collateral ligament in rabbits. J Orthop Res 26:1098–1104

    Article  CAS  PubMed  Google Scholar 

  • Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA, Gewirtz AM, Emerson SG, Ratajczak MZ (2001) Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 97:3075–3085

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto T, Kawamoto A, Kuroda R, Ishikawa M, Mifune Y, Iwasaki H, Miwa M, Horii M, Hayashi S, Oyamada A, Nishimura H, Murasawa S, Doita M, Kurosaka M, Asahara T (2006) Therapeutic potential of vasculogenesis and osteogenesis promoted by peripheral blood CD34-positive cells for functional bone healing. Am J Pathol 169:1440–1457

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mifune Y, Matsumoto T, Ota S, Nishimori M, Usas A, Kopf S, Kuroda R, Kurosaka M, Fu FH, Huard J (2012) Therapeutic potential of anterior cruciate ligament-derived stem cells for anterior cruciate ligament reconstruction. Cell Transplant 21:1651–1665

    Article  PubMed  Google Scholar 

  • Mifune Y, Matsumoto T, Takayama K, Terada S, Sekiya N, Kuroda R, Kurosaka M, Fu FH, Huard J (2013) Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34+ cell sheets for ACL reconstruction. Biomaterials 34:5476–5487

    Article  CAS  PubMed  Google Scholar 

  • Ni M, Lui PP, Rui YF, Lee YW, Lee YW, Tan Q, Wong YM, Kong SK, Lau PM, Li G, Chan KM (2012) Tendon-derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model. J Orthop Res 30:613–619

    Article  CAS  PubMed  Google Scholar 

  • Nishimori M, Matsumoto T, Ota S, Kopf S, Mifune Y, Harner C, Ochi M, Fu FH, Huard J (2012) Role of angiogenesis after muscle derived stem cell transplantation in injured medial collateral ligament. J Orthop Res 30:627–633

    Article  CAS  PubMed  Google Scholar 

  • Peng LH, Mao ZY, Qi XT, Chen X, Li N, Tabata Y, Gao JQ (2013) Transplantation of bone-marrow-derived mesenchymal and epidermal stem cells contribute to wound healing with different regenerative features. Cell Tissue Res 352:573–583

    Article  CAS  PubMed  Google Scholar 

  • Rosenkranz K, Kumbruch S, Tenbusch M, Marcus K, Marschner K, Dermietzel R, Meier C (2012) Transplantation of human umbilical cord blood cells mediated beneficial effects on apoptosis, angiogenesis and neuronal survival after hypoxic-ischemic brain injury in rats. Cell Tissue Res 348:429–438

    Article  CAS  PubMed  Google Scholar 

  • Saiga K, Furumatsu T, Yoshida A, Masuda S, Takihira S, Abe N, Ozaki T (2010) Combined use of bFGF and GDF-5 enhances the healing of medial collateral ligament injury. Biochem Biophys Res Commun 402:329–334

    Article  CAS  PubMed  Google Scholar 

  • Schuleri KH, Feigenbaum GS, Centola M, Weiss ES, Zimmet JM, Turney J, Kellner J, Zviman MM, Hatzistergos KE, Detrick B, Conte JV, McNiece I, Steenbergen C, Lardo AC, Hare JM (2009) Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy. Eur Heart J 30:2722–2732

    Article  PubMed Central  PubMed  Google Scholar 

  • Tei K, Matsumoto T, Mifune Y, Ishida K, Sasaki K, Shoji T, Kubo S, Kawamoto A, Asahara T, Kurosaka M, Kuroda R (2008) Administrations of peripheral blood CD34-positive cells contribute to medial collateral ligament healing via vasculogenesis. Stem Cells 26:819–830

    Article  CAS  PubMed  Google Scholar 

  • Watanabe N, Woo SL, Papageorgiou C, Celechovsky C, Takai S (2002) Fate of donor bone marrow cells in medial collateral ligament after simulated autologous transplantation. Microsc Res Tech 58:39–44

    Article  PubMed  Google Scholar 

  • Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW, Hare JM (2013) Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 127:213–223

    Article  PubMed Central  PubMed  Google Scholar 

  • Woo SL, Inoue M, McGurk-Burleson E, Gomez MA (1987) Treatment of the medial collateral ligament injury. II. Structure and function of canine knees in response to differing treatment regimens. Am J Sports Med 15:22–29

    Article  CAS  PubMed  Google Scholar 

  • Xu B, Yang M, Li Z, Zhang Y, Jiang Z, Guan S, Jiang D (2013) Thymosin beta4 enhances the healing of medial collateral ligament injury in rat. Regul Pept 184:1–5

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Pan T, Im HJ, Fu FH, Wang JH (2011) Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity. BMC Med 9:68

    Article  PubMed Central  PubMed  Google Scholar 

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Correspondence to Hongquan Geng.

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This work was supported by grants from the National Natural Sciences Foundation of China (nos. 30901516, 81472085).

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Jiang, D., Yang, S., Gao, P. et al. Combined effect of ligament stem cells and umbilical-cord-blood-derived CD34+ cells on ligament healing. Cell Tissue Res 362, 587–595 (2015). https://doi.org/10.1007/s00441-015-2250-4

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  • DOI: https://doi.org/10.1007/s00441-015-2250-4

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