FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / PLoS One / Hypoxia and mesenchymal stromal cells as key drivers of init...
PloS one2019; 14(4); e0214276; doi: 10.1371/journal.pone.0214276

Hypoxia and mesenchymal stromal cells as key drivers of initial fracture healing in an equine in vitro fracture hematoma model.

Abstract: Fractures in horses-whether simple fractures with just one clean break, or incomplete greenstick with stress fractures, or complications such as shattered bones can all be either minimal or even catastrophic. Thus, improvement in fracture healing is a hallmark in equine orthopedics. The fracture healing process implements a complex sequence of events including the initial inflammatory phase removing damaged tissue, re-establishment of vessels and mesenchymal stromal cells, a soft and hard callus phase closing the fracture gap as well as the remodeling phase shaping the bone to a scar-free tissue. Detailed knowledge on processes in equine fracture healing in general and on the initial phase in particular is apparently very limited. Therefore, we generated equine in vitro fracture hematoma models (FH models) to study time-dependent changes in cell composition and RNA-expression for the most prominent cells in the FH model (immune cells, mesenchymal stromal cells) under conditions most closely adapted to the in vivo situation (hypoxia) by using flow cytometry and qPCR. In order to analyze the impact of mesenchymal stromal cells in greater detail, we also incubated blood clots without the addition of mesenchymal stromal cells under the same conditions as a control. We observed a superior survival capacity of mesenchymal stromal cells over immune cells within our FH model maintained under hypoxia. Furthermore, we demonstrate an upregulation of relevant angiogenic, osteogenic and hypoxia-induced markers within 48 h, a time well-known to be crucial for proper fracture healing.
Get Full Text
Publication Date: 2019-04-04 PubMed ID: 30947253PubMed Central: PMC6449067DOI: 10.1371/journal.pone.0214276Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research studied the healing process of fractures in horses using in vitro models to better understand the role of mesenchymal stromal cells and hypoxia. It revealed that mesenchymal stromal cells have better survival capability under hypoxia and play a key role in promoting angiogenesis, osteogenesis and fracture healing.

Overview of the Research

  • This research attempted to boost the understanding of fracture healing in horses. The healing process of fractures involves many steps including inflammation, regeneration of the blood vessels, action of mesenchymal stromal cells and formation of bone tissue.
  • The researchers acknowledged that there is limited knowledge available regarding the initial phase of fracture healing.

Methodology

  • Equine in vitro fracture hematoma models were used in this study, also known as FH models. These helped the researchers study the changes in cell composition and RNA expression over time under hypoxia – a condition that most closely resembles that of an injured horse.
  • The main focus was on mesenchymal stromal cells and immune cells, and how these responded in the situation of low oxygen supply. Their responses were analyzed using flow cytometry and qPCR (quantitative Polymerase Chain Reaction).
  • To study the mesenchymal stromal cells more closely, the researchers also introduced a control group that lacked these cells.

Findings

  • It was observed that mesenchymal stromal cells survived better than immune cells in hypoxic conditions.
  • Data indicated an increase in angiogenic, osteogenic and hypoxia-induced markers within 48 hours, a period considered to be critical for successful fracture healing.

Significance of Results

  • The findings of this study are significant as they could lead to improvements in equine orthopedics in terms of fracture healing.
  • Understanding more about the survival capacity of mesenchymal stromal cells under hypoxia and their role in fracture healing could help develop better therapeutic methods or interventions.

Cite This Article

APA
Pfeiffenberger M, Bartsch J, Hoff P, Ponomarev I, Barnewitz D, Thöne-Reineke C, Buttgereit F, Gaber T, Lang A. (2019). Hypoxia and mesenchymal stromal cells as key drivers of initial fracture healing in an equine in vitro fracture hematoma model. PLoS One, 14(4), e0214276. https://doi.org/10.1371/journal.pone.0214276

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 14
Issue: 4
Pages: e0214276
PII: e0214276

Researcher Affiliations

Pfeiffenberger, Moritz
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Bartsch, Janika
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Hoff, Paula
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Ponomarev, Igor
  • Research Center of Medical Technology and Biotechnology, Bad Langensalza, Germany.
Barnewitz, Dirk
  • Research Center of Medical Technology and Biotechnology, Bad Langensalza, Germany.
Thöne-Reineke, Christa
  • Institute of Animal Welfare, Animal Behavior and Laboratory Animal Science, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
Buttgereit, Frank
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Gaber, Timo
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.
Lang, Annemarie
  • Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Rheumatism Research Centre (DRFZ) Berlin, a Leibniz Institute, Berlin, Germany.

MeSH Terms

  • Animals
  • Biomarkers / metabolism
  • Biopsy
  • Cell Survival / drug effects
  • Fracture Healing / drug effects
  • Fractures, Bone / pathology
  • Fractures, Bone / therapy
  • Hematoma / pathology
  • Hematoma / therapy
  • Horses
  • Hypoxia / pathology
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Models, Biological
  • Neovascularization, Physiologic / drug effects
  • Osteogenesis / drug effects
  • Oxygen / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Time Factors
  • Up-Regulation / drug effects

Conflict of Interest Statement

The authors have declared that no competing interests exist.

References

This article includes 70 references
  1. Auer JA, Grainger DW. Fracture management in horses: Where have we been and where are we going?. Vet J 2015 Oct;206(1):5-14.
    doi: 10.1016/j.tvjl.2015.06.002pubmed: 26095036google scholar: lookup
  2. Rosanowski SM, Chang YM, Stirk AJ, Verheyen KLP. Risk factors for race-day fatality in flat racing Thoroughbreds in Great Britain (2000 to 2013).. PLoS One 2018;13(3):e0194299.
    doi: 10.1371/journal.pone.0194299pmc: PMC5862470pubmed: 29561898google scholar: lookup
  3. Peloso JG, Mundy GD, Cohen ND. Prevalence of, and factors associated with, musculoskeletal racing injuries of thoroughbreds.. J Am Vet Med Assoc 1994 Feb 15;204(4):620-6.
    pubmed: 8163419
  4. Maeda Y, Hanada M, Oikawa MA. Epidemiology of racing injuries in Thoroughbred racehorses with special reference to bone fractures: Japanese experience from the 1980s to 2000s.. J Equine Sci 2016;27(3):81-97.
    doi: 10.1294/jes.27.81pmc: PMC5048355pubmed: 27703403google scholar: lookup
  5. Verheyen KL, Wood JL. Descriptive epidemiology of fractures occurring in British Thoroughbred racehorses in training.. Equine Vet J 2004 Mar;36(2):167-73.
    pubmed: 15038441doi: 10.2746/0425164044868684google scholar: lookup
  6. Janczarek I, Wilk I. Leisure riding horses: research topics versus the needs of stakeholders.. Anim Sci J 2017 Jul;88(7):953-958.
    doi: 10.1111/asj.12800pubmed: 28422370google scholar: lookup
  7. Mejdell CM, Jørgensen GH, Rehn T, Fremstad K, Keeling L, Bøe KE. Reliability of an injury scoring system for horses.. Acta Vet Scand 2010 Dec 31;52(1):68.
    doi: 10.1186/1751-0147-52-68pmc: PMC3023730pubmed: 21194451google scholar: lookup
  8. Auer JA. Principles of Fracture Treatment. Equine Surgery (Third Edition) 2006 p. 1000–29.
  9. Auer JA, Watkins JP. Treatment of radial fractures in adult horses: an analysis of 15 clinical cases.. Equine Vet J 1987 Mar;19(2):103-10.
    pubmed: 3569192doi: 10.1111/j.2042-3306.1987.tb02601.xgoogle scholar: lookup
  10. Jacobs CC, Levine DG, Richardson DW. Use of locking compression plates in ulnar fractures of 18 horses.. Vet Surg 2017 Feb;46(2):242-248.
    doi: 10.1111/vsu.12607pubmed: 28146292google scholar: lookup
  11. Turek B, Potynski A, Drewnowska O. Own-design external fixator for the treatment of diaphyseal fractures of the third metacarpal bone in horses. Med Weter 2016;72(3):197–202.
  12. Cohen JM, Southwood LL, Engiles J, Leitch M, Nunamaker DM. Effects of a novel hydrogel on equine bone healing: a pilot study.. Vet Comp Orthop Traumatol 2012;25(3):184-91.
    doi: 10.3415/VCOT-11-01-0006pubmed: 22366873google scholar: lookup
  13. Govoni KE. HORSE SPECIES SYMPOSIUM: Use of mesenchymal stem cells in fracture repair in horses.. J Anim Sci 2015 Mar;93(3):871-8.
    doi: 10.2527/jas.2014-8516pubmed: 26020865google scholar: lookup
  14. Rosset P, Deschaseaux F, Layrolle P. Cell therapy for bone repair.. Orthop Traumatol Surg Res 2014 Feb;100(1 Suppl):S107-12.
    doi: 10.1016/j.otsr.2013.11.010pubmed: 24411717google scholar: lookup
  15. McD￮ LA, Pack L, Lores M, Wright GM, Esparza-Gonzalez B, Masaoud E. Osteoprogenitor cell therapy in an equine fracture model.. Vet Surg 2012 Oct;41(7):773-83.
    doi: 10.1111/j.1532-950X.2012.01024.xpubmed: 22804243google scholar: lookup
  16. Murphey ED, Schneider RK, Adams SB, Santschi EM, Stick JA, Ruggles AJ. Long-term outcome of horses with a slab fracture of the central or third tarsal bone treated conservatively: 25 cases (1976-1993).. J Am Vet Med Assoc 2000 Jun 15;216(12):1949-54.
    pubmed: 10863595doi: 10.2460/javma.2000.216.1949google scholar: lookup
  17. Enneking WF, Burchardt H, Puhl JJ, Piotrowski G. Physical and biological aspects of repair in dog cortical-bone transplants.. J Bone Joint Surg Am 1975 Mar;57(2):237-52.
    pubmed: 1089671
  18. Kolar P, Gaber T, Perka C, Duda GN, Buttgereit F. Human early fracture hematoma is characterized by inflammation and hypoxia.. Clin Orthop Relat Res 2011 Nov;469(11):3118-26.
    doi: 10.1007/s11999-011-1865-3pmc: PMC3183184pubmed: 21409457google scholar: lookup
  19. Schmidt-Bleek K, Schell H, Kolar P, Pfaff M, Perka C, Buttgereit F, Duda G, Lienau J. Cellular composition of the initial fracture hematoma compared to a muscle hematoma: a study in sheep.. J Orthop Res 2009 Sep;27(9):1147-51.
    doi: 10.1002/jor.20901pubmed: 19382195google scholar: lookup
  20. Martini L, Fini M, Giavaresi G, Giardino R. Sheep model in orthopedic research: a literature review.. Comp Med 2001 Aug;51(4):292-9.
    pubmed: 11924786
  21. Holstein JH, Garcia P, Histing T, Kristen A, Scheuer C, Menger MD, Pohlemann T. Advances in the establishment of defined mouse models for the study of fracture healing and bone regeneration.. J Orthop Trauma 2009 May-Jun;23(5 Suppl):S31-8.
    doi: 10.1097/BOT.0b013e31819f27e5pubmed: 19390374google scholar: lookup
  22. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, Finnerty CC, López CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller-Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG. Genomic responses in mouse models poorly mimic human inflammatory diseases.. Proc Natl Acad Sci U S A 2013 Feb 26;110(9):3507-12.
    doi: 10.1073/pnas.1222878110pmc: PMC3587220pubmed: 23401516google scholar: lookup
  23. Pearce AI, Richards RG, Milz S, Schneider E, Pearce SG. Animal models for implant biomaterial research in bone: a review.. Eur Cell Mater 2007 Mar 2;13:1-10.
    pubmed: 17334975doi: 10.22203/ecm.v013a01google scholar: lookup
  24. Marsell R, Einhorn TA. The biology of fracture healing.. Injury 2011 Jun;42(6):551-5.
    doi: 10.1016/j.injury.2011.03.031pmc: PMC3105171pubmed: 21489527google scholar: lookup
  25. Hoff P, Gaber T, Strehl C, Jakstadt M, Hoff H, Schmidt-Bleek K, Lang A, Röhner E, Huscher D, Matziolis G, Burmester GR, Schmidmaier G, Perka C, Duda GN, Buttgereit F. A Pronounced Inflammatory Activity Characterizes the Early Fracture Healing Phase in Immunologically Restricted Patients.. Int J Mol Sci 2017 Mar 8;18(3).
    doi: 10.3390/ijms18030583pmc: PMC5372599pubmed: 28282868google scholar: lookup
  26. Klenke S, Renckhoff K, Engler A, Peters J, Frey UH. Easy-to-use strategy for reference gene selection in quantitative real-time PCR experiments.. Naunyn Schmiedebergs Arch Pharmacol 2016 Dec;389(12):1353-1366.
    doi: 10.1007/s00210-016-1305-8pubmed: 27650728google scholar: lookup
  27. Baddela VS, Baufeld A, Yenuganti VR, Vanselow J, Singh D. Suitable housekeeping genes for normalization of transcript abundance analysis by real-time RT-PCR in cultured bovine granulosa cells during hypoxia and differential cell plating density.. Reprod Biol Endocrinol 2014 Nov 27;12:118.
    doi: 10.1186/1477-7827-12-118pmc: PMC4280684pubmed: 25430436google scholar: lookup
  28. Kawamoto T, Kawamoto K. Preparation of thin frozen sections from nonfixed and undecalcified hard tissues using Kawamot's film method (2012).. Methods Mol Biol 2014;1130:149-164.
    doi: 10.1007/978-1-62703-989-5_11pubmed: 24482171google scholar: lookup
  29. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.. Cytotherapy 2006;8(4):315-7.
    doi: 10.1080/14653240600855905pubmed: 16923606google scholar: lookup
  30. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells.. Science 1999 Apr 2;284(5411):143-7.
    doi: 10.1126/science.284.5411.143pubmed: 10102814google scholar: lookup
  31. De Schauwer C, van de Walle GR, Piepers S, Hoogewijs MK, Govaere JL, Meyer E, van Soom A. Successful isolation of equine mesenchymal stromal cells from cryopreserved umbilical cord blood-derived mononuclear cell fractions.. Equine Vet J 2013 Jul;45(4):518-22.
    doi: 10.1111/evj.12003pubmed: 23206252google scholar: lookup
  32. Maia L, Landim-Alvarenga FC, Da Mota LS, De Assis Golim M, Laufer-Amorim R, De Vita B, Barberini DJ, Listoni AJ, De Moraes CN, Heckler MC, Amorim RM. Immunophenotypic, immunocytochemistry, ultrastructural, and cytogenetic characterization of mesenchymal stem cells from equine bone marrow.. Microsc Res Tech 2013 Jun;76(6):618-24.
    doi: 10.1002/jemt.22208pubmed: 23533133google scholar: lookup
  33. Radtke CL, Nino-Fong R, Esparza Gonzalez BP, Stryhn H, McD￮ LA. Characterization and osteogenic potential of equine muscle tissue- and periosteal tissue-derived mesenchymal stem cells in comparison with bone marrow- and adipose tissue-derived mesenchymal stem cells.. Am J Vet Res 2013 May;74(5):790-800.
    doi: 10.2460/ajvr.74.5.790pubmed: 23627394google scholar: lookup
  34. Ranera B, Remacha AR, Álvarez-Arguedas S, Romero A, Vázquez FJ, Zaragoza P, Martín-Burriel I, Rodellar C. Effect of hypoxia on equine mesenchymal stem cells derived from bone marrow and adipose tissue.. BMC Vet Res 2012 Aug 22;8:142.
    doi: 10.1186/1746-6148-8-142pmc: PMC3483288pubmed: 22913590google scholar: lookup
  35. Barberini DJ, Freitas NP, Magnoni MS, Maia L, Listoni AJ, Heckler MC, Sudano MJ, Golim MA, da Cruz Landim-Alvarenga F, Amorim RM. Equine mesenchymal stem cells from bone marrow, adipose tissue and umbilical cord: immunophenotypic characterization and differentiation potential.. Stem Cell Res Ther 2014 Feb 21;5(1):25.
    doi: 10.1186/scrt414pmc: PMC4055040pubmed: 24559797google scholar: lookup
  36. Paebst F, Piehler D, Brehm W, Heller S, Schroeck C, Tárnok A, Burk J. Comparative immunophenotyping of equine multipotent mesenchymal stromal cells: an approach toward a standardized definition.. Cytometry A 2014 Aug;85(8):678-87.
    doi: 10.1002/cyto.a.22491pubmed: 24894974google scholar: lookup
  37. Treonze KM, Alves K, Fischer P, Hagmann WK, Hora D, Kulick A, Vakerich K, Smith ND, Lingham RB, Maniar S, Reger TS, Zunic J, Munoz B, Prasit P, Nicholson D, Si Q, Judd K, Nicolich S, Kellerhouse P, Thompson D, Mumford RA. Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction).. Vet Immunol Immunopathol 2009 Jul 15;130(1-2):79-87.
    doi: 10.1016/j.vetimm.2009.01.011pubmed: 19250687google scholar: lookup
  38. De Schauwer C, Piepers S, Van de Walle GR, Demeyere K, Hoogewijs MK, Govaere JL, Braeckmans K, Van Soom A, Meyer E. In search for cross-reactivity to immunophenotype equine mesenchymal stromal cells by multicolor flow cytometry.. Cytometry A 2012 Apr;81(4):312-23.
    doi: 10.1002/cyto.a.22026pubmed: 22411893google scholar: lookup
  39. Yeo WM, Osterrieder N, Stokol T. Equine herpesvirus type 1 infection induces procoagulant activity in equine monocytes.. Vet Res 2013 Mar 11;44(1):16.
    doi: 10.1186/1297-9716-44-16pmc: PMC3618259pubmed: 23497076google scholar: lookup
  40. Keramaris NC, Kaptanis S, Moss HL, Loppini M, Pneumaticos S, Maffulli N. Endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) in bone healing.. Curr Stem Cell Res Ther 2012 Jul;7(4):293-301.
    pubmed: 22563666doi: 10.2174/157488812800793081google scholar: lookup
  41. Knight MN, Hankenson KD. Mesenchymal Stem Cells in Bone Regeneration.. Adv Wound Care (New Rochelle) 2013 Jul;2(6):306-316.
    doi: 10.1089/wound.2012.0420pmc: PMC3842877pubmed: 24527352google scholar: lookup
  42. Kovach TK, Dighe AS, Lobo PI, Cui Q. Interactions between MSCs and immune cells: implications for bone healing.. J Immunol Res 2015;2015:752510.
    doi: 10.1155/2015/752510pmc: PMC4427002pubmed: 26000315google scholar: lookup
  43. Wagegg M, Gaber T, Lohanatha FL, Hahne M, Strehl C, Fangradt M, Tran CL, Schönbeck K, Hoff P, Ode A, Perka C, Duda GN, Buttgereit F. Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner.. PLoS One 2012;7(9):e46483.
    doi: 10.1371/journal.pone.0046483pmc: PMC3459928pubmed: 23029528google scholar: lookup
  44. Kovtun A, Bergdolt S, Wiegner R, Radermacher P, Huber-Lang M, Ignatius A. The crucial role of neutrophil granulocytes in bone fracture healing.. Eur Cell Mater 2016 Jul 25;32:152-62.
    pubmed: 27452963doi: 10.22203/ecm.v032a10google scholar: lookup
  45. Grøgaard B, Gerdin B, Reikerås O. The polymorphonuclear leukocyte: has it a role in fracture healing?. Arch Orthop Trauma Surg 1990;109(5):268-71.
    doi: 10.1007/bf00419942pubmed: 2271360google scholar: lookup
  46. Chung R, Cool JC, Scherer MA, Foster BK, Xian CJ. Roles of neutrophil-mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats.. J Leukoc Biol 2006 Dec;80(6):1272-80.
    doi: 10.1189/jlb.0606365pubmed: 16959896google scholar: lookup
  47. Hoff P, Maschmeyer P, Gaber T, Schütze T, Raue T, Schmidt-Bleek K, Dziurla R, Schellmann S, Lohanatha FL, Röhner E, Ode A, Burmester GR, Duda GN, Perka C, Buttgereit F. Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model.. Cell Mol Immunol 2013 Mar;10(2):151-8.
    doi: 10.1038/cmi.2012.56pmc: PMC4003042pubmed: 23396474google scholar: lookup
  48. Soehnlein O, Lindbom L, Weber C. Mechanisms underlying neutrophil-mediated monocyte recruitment.. Blood 2009 Nov 19;114(21):4613-23.
    doi: 10.1182/blood-2009-06-221630pubmed: 19696199google scholar: lookup
  49. Toben D, Schroeder I, El Khassawna T, Mehta M, Hoffmann JE, Frisch JT, Schell H, Lienau J, Serra A, Radbruch A, Duda GN. Fracture healing is accelerated in the absence of the adaptive immune system.. J Bone Miner Res 2011 Jan;26(1):113-24.
    doi: 10.1002/jbmr.185pubmed: 20641004google scholar: lookup
  50. Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, Akyüz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD, Duda GN. Terminally differentiated CD8⁺ T cells negatively affect bone regeneration in humans.. Sci Transl Med 2013 Mar 20;5(177):177ra36.
    doi: 10.1126/scitranslmed.3004754pubmed: 23515078google scholar: lookup
  51. Vuillefroy de Silly R, Ducimetière L, Yacoub Maroun C, Dietrich PY, Derouazi M, Walker PR. Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells.. Eur J Immunol 2015 Aug;45(8):2263-75.
    doi: 10.1002/eji.201445284pmc: PMC7163737pubmed: 25929785google scholar: lookup
  52. De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F. Immunosuppressive properties of mesenchymal stem cells: advances and applications.. Curr Mol Med 2012 Jun;12(5):574-91.
    pubmed: 22515979doi: 10.2174/156652412800619950google scholar: lookup
  53. Faiella W, Atoui R. Immunotolerant Properties of Mesenchymal Stem Cells: Updated Review.. Stem Cells Int 2016;2016:1859567.
    doi: 10.1155/2016/1859567pmc: PMC4709780pubmed: 26839557google scholar: lookup
  54. Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways.. Stem Cell Res Ther 2011 Aug 11;2(4):34.
    doi: 10.1186/scrt75pmc: PMC3219065pubmed: 21861858google scholar: lookup
  55. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells.. Blood 2007 Nov 15;110(10):3499-506.
    doi: 10.1182/blood-2007-02-069716pubmed: 17664353google scholar: lookup
  56. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens.. J Immunol 2003 Oct 1;171(7):3426-34.
    pubmed: 14500637doi: 10.4049/jimmunol.171.7.3426google scholar: lookup
  57. Robey IF, Lien AD, Welsh SJ, Baggett BK, Gillies RJ. Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors.. Neoplasia 2005 Apr;7(4):324-30.
    pmc: PMC1501147pubmed: 15967109doi: 10.1593/neo.04430google scholar: lookup
  58. Ito K, Suda T. Metabolic requirements for the maintenance of self-renewing stem cells.. Nat Rev Mol Cell Biol 2014 Apr;15(4):243-56.
    doi: 10.1038/nrm3772pmc: PMC4095859pubmed: 24651542google scholar: lookup
  59. Gaber T, Dziurla R, Tripmacher R, Burmester GR, Buttgereit F. Hypoxia inducible factor (HIF) in rheumatology: low O2! See what HIF can do!. Ann Rheum Dis 2005 Jul;64(7):971-80.
    doi: 10.1136/ard.2004.031641pmc: PMC1755583pubmed: 15800008google scholar: lookup
  60. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1.. Annu Rev Cell Dev Biol 1999;15:551-78.
    doi: 10.1146/annurev.cellbio.15.1.551pubmed: 10611972google scholar: lookup
  61. Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R, Ferrara N, Olsen BR. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation.. J Clin Invest 2012 Sep;122(9):3101-13.
    doi: 10.1172/JCI61209pmc: PMC3428080pubmed: 22886301google scholar: lookup
  62. Berendsen AD, Olsen BR. How vascular endothelial growth factor-A (VEGF) regulates differentiation of mesenchymal stem cells.. J Histochem Cytochem 2014 Feb;62(2):103-8.
    doi: 10.1369/0022155413516347pmc: PMC3902099pubmed: 24309509google scholar: lookup
  63. Köttstorfer J, Kaiser G, Thomas A, Gregori M, Kecht M, Domaszewski F, Sarahrudi K. The influence of non-osteogenic factors on the expression of M-CSF and VEGF during fracture healing.. Injury 2013 Jul;44(7):930-4.
    doi: 10.1016/j.injury.2013.02.028pubmed: 23570706google scholar: lookup
  64. Ochman S, Frey S, Raschke MJ, Deventer JN, Meffert RH. Local application of VEGF compensates callus deficiency after acute soft tissue trauma--results using a limb-shortening distraction procedure in rabbit tibia.. J Orthop Res 2011 Jul;29(7):1093-8.
    doi: 10.1002/jor.21340pubmed: 21284032google scholar: lookup
  65. Wang CJ, Huang KE, Sun YC, Yang YJ, Ko JY, Weng LH, Wang FS. VEGF modulates angiogenesis and osteogenesis in shockwave-promoted fracture healing in rabbits.. J Surg Res 2011 Nov;171(1):114-9.
    doi: 10.1016/j.jss.2010.01.045pubmed: 20452608google scholar: lookup
  66. Schmidt-Bleek K, Schell H, Lienau J, Schulz N, Hoff P, Pfaff M, Schmidt G, Martin C, Perka C, Buttgereit F, Volk HD, Duda G. Initial immune reaction and angiogenesis in bone healing.. J Tissue Eng Regen Med 2014 Feb;8(2):120-30.
    doi: 10.1002/term.1505pubmed: 22495762google scholar: lookup
  67. Kobayashi T, Onodera S, Kondo E, Tohyama H, Fujiki H, Yokoyama A, Yasuda K. Impaired fracture healing in macrophage migration inhibitory factor-deficient mice.. Osteoporos Int 2011 Jun;22(6):1955-65.
    doi: 10.1007/s00198-010-1385-0pubmed: 20838768google scholar: lookup
  68. Onodera S, Nishihira J, Yamazaki M, Ishibashi T, Minami A. Increased expression of macrophage migration inhibitory factor during fracture healing in rats.. Histochem Cell Biol 2004 Mar;121(3):209-17.
    doi: 10.1007/s00418-004-0624-xpubmed: 14767776google scholar: lookup
  69. Liu CH, Hwang SM. Cytokine interactions in mesenchymal stem cells from cord blood.. Cytokine 2005 Dec 21;32(6):270-9.
    doi: 10.1016/j.cyto.2005.11.003pubmed: 16377203google scholar: lookup
  70. Xia W, Xie C, Jiang M, Hou M. Improved survival of mesenchymal stem cells by macrophage migration inhibitory factor.. Mol Cell Biochem 2015 Jun;404(1-2):11-24.
    doi: 10.1007/s11010-015-2361-ypmc: PMC4544672pubmed: 25701358google scholar: lookup

Citations

This article has been cited 14 times.
  1. Malhan D, Schmidt-Bleek K, Duda GN, El Khassawna T. Landscape of Well-Coordinated Fracture Healing in a Mouse Model Using Molecular and Cellular Analysis.. Int J Mol Sci 2023 Feb 10;24(4).
    doi: 10.3390/ijms24043569pubmed: 36834981google scholar: lookup
  2. Trivanovic D, Volkmann N, Stoeckl M, Tertel T, Rudert M, Giebel B, Herrmann M. Enhancement of Immunosuppressive Activity of Mesenchymal Stromal Cells by Platelet-Derived Factors is Accompanied by Apoptotic Priming.. Stem Cell Rev Rep 2023 Apr;19(3):713-733.
    doi: 10.1007/s12015-022-10471-4pubmed: 36417151google scholar: lookup
  3. Bagge J, Berg LC, Janes J, MacLeod JN. Donor age effects on in vitro chondrogenic and osteogenic differentiation performance of equine bone marrow- and adipose tissue-derived mesenchymal stromal cells.. BMC Vet Res 2022 Nov 3;18(1):388.
    doi: 10.1186/s12917-022-03475-2pubmed: 36329434google scholar: lookup
  4. Liu C, Rinderknecht H, Histing T, Kolbenschlag J, Nussler AK, Ehnert S. Establishment of an In Vitro Scab Model for Investigating Different Phases of Wound Healing.. Bioengineering (Basel) 2022 Apr 28;9(5).
    doi: 10.3390/bioengineering9050191pubmed: 35621469google scholar: lookup
  5. Rinderknecht H, Nussler AK, Steinestel K, Histing T, Ehnert S. Smoking Impairs Hematoma Formation and Dysregulates Angiogenesis as the First Steps of Fracture Healing.. Bioengineering (Basel) 2022 Apr 24;9(5).
    doi: 10.3390/bioengineering9050186pubmed: 35621464google scholar: lookup
  6. Cequier A, Romero A, Vázquez FJ, Vitoria A, Bernad E, Fuente S, Zaragoza P, Rodellar C, Barrachina L. Equine Mesenchymal Stem Cells Influence the Proliferative Response of Lymphocytes: Effect of Inflammation, Differentiation and MHC-Compatibility.. Animals (Basel) 2022 Apr 11;12(8).
    doi: 10.3390/ani12080984pubmed: 35454231google scholar: lookup
  7. Löhning M, Shen P, Dzamukova M, Durán-Hernández N, Roodselaar J, Hauser AE, Fiedler A, Niesner RA, Gaber T, Buttgereit F. [The DRFZ-a pioneer in research on the interaction between immune and stromal cells during de- and regeneration of the musculoskeletal system].. Z Rheumatol 2022 Oct;81(8):652-659.
    doi: 10.1007/s00393-022-01188-3pubmed: 35412048google scholar: lookup
  8. Uberti B, Plaza A, Henríquez C. Pre-conditioning Strategies for Mesenchymal Stromal/Stem Cells in Inflammatory Conditions of Livestock Species.. Front Vet Sci 2022;9:806069.
    doi: 10.3389/fvets.2022.806069pubmed: 35372550google scholar: lookup
  9. Al Hosni R, Bozec L, Roberts SJ, Cheema U. Reprogramming bone progenitor identity and potency through control of collagen density and oxygen tension.. iScience 2022 Apr 15;25(4):104059.
    doi: 10.1016/j.isci.2022.104059pubmed: 35345460google scholar: lookup
  10. Pfeiffenberger M, Damerau A, Lang A, Buttgereit F, Hoff P, Gaber T. Fracture Healing Research-Shift towards In Vitro Modeling?. Biomedicines 2021 Jun 28;9(7).
    doi: 10.3390/biomedicines9070748pubmed: 34203470google scholar: lookup
  11. Ribitsch I, Oreff GL, Jenner F. Regenerative Medicine for Equine Musculoskeletal Diseases.. Animals (Basel) 2021 Jan 19;11(1).
    doi: 10.3390/ani11010234pubmed: 33477808google scholar: lookup
  12. Bagge J, MacLeod JN, Berg LC. Cellular Proliferation of Equine Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem Cells Decline With Increasing Donor Age.. Front Vet Sci 2020;7:602403.
    doi: 10.3389/fvets.2020.602403pubmed: 33363241google scholar: lookup
  13. Marx-Stoelting P, Solano MLM, Aoyama H, Adams RH, Bal-Price A, Buschmann J, Chahoud I, Clark R, Fang T, Fujiwara M, Gelinsky M, Grote K, Horimoto M, Bennekou SH, Kellner R, Kuwagata M, Leist M, Lang A, Li W, Mantovani A, Makris SL, Paumgartten F, Perron M, Sachana M, Schmitt A, Schneider S, Schönfelder G, Schulze F, Shiota K, Solecki R. 25th anniversary of the Berlin workshop on developmental toxicology: DevTox database update, challenges in risk assessment of developmental neurotoxicity and alternative methodologies in bone development and growth.. Reprod Toxicol 2021 Mar;100:155-162.
    doi: 10.1016/j.reprotox.2020.11.003pubmed: 33278556google scholar: lookup
  14. Ehnert S, Rinderknecht H, Aspera-Werz RH, Häussling V, Nussler AK. Use of in vitro bone models to screen for altered bone metabolism, osteopathies, and fracture healing: challenges of complex models.. Arch Toxicol 2020 Dec;94(12):3937-3958.
    doi: 10.1007/s00204-020-02906-zpubmed: 32910238google scholar: lookup
Subscribe to our newsletter
Join 99,344 horse owners like you who receive our email updates on horse health and nutrition.