Transforming Growth Factor-β2 Downregulates Major Histocompatibility Complex (MHC) I and MHC II Surface Expression on Equine Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Other Phenotypic Cell Surface Markers.
Abstract: Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Effective and safe allogeneic therapy may be hindered, however, by recipient immune recognition and rejection of major histocompatibility complex (MHC)-mismatched MSCs. Development of strategies to prevent immune rejection of MHC-mismatched MSCs in vivo is necessary to enhance cell survival and potentially increase the efficacy and safety of allogeneic MSC therapy. The purposes of this study were to evaluate if transforming growth factor-β2 (TGF-β2) downregulated MHC expression on equine MSCs and to determine if TGF-β2 treatment altered the phenotype of MSCs. Equine bone marrow-derived MSCs from 12 horses were treated with 1, 5, or 10 ng/ml TGF-β2 from initial isolation until MHC expression analysis. TGF-β2-treated MSCs had reduced MHC I and MHC II surface expression compared to untreated controls. TGF-β2 treatment also partially blocked IFN-γ-induced upregulation of MHC I and MHC II. Constitutive and IFN-γ-induced MHC I and MHC II expression on equine MSCs was dynamic and highly variable, and the effect of TGF-β2 was significantly dependent on the donor animal and baseline MHC expression. TGF-β2 treatment did not appear to change morphology, surface marker expression, MSC viability, or secretion of TGF-β1, but did significantly increase the number of cells obtained from culture. These results indicate that TGF-β2 treatment has promise for regulating MHC expression on MSCs to facilitate allogeneic therapy, but further work is needed to maintain MHC stability when exposed to an inflammatory stimulus.
Publication Date: 2017-06-12 PubMed ID: 28660198PubMed Central: PMC5466990DOI: 10.3389/fvets.2017.00084Google 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.
- Journal Article
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.
The study focuses on the impact of a particular growth factor (TGF-β2) on the presentation of Major Histocompatibility Complex (MHC) on the surface of mesenchymal stem cells (MSCs) derived from horse bone marrow. The researchers found the growth factor may assist in regulating MHC, potentially leading to more successful use of allogeneic (donor) stem cell therapy in equine treatment, though more work is needed to maintain MHC stability when under inflammatory stress.
Research Background
- The issue at the heart of this research is the challenge in using allogeneic mesenchymal stem cells (MSCs) in the treatment of musculoskeletal injuries in horses.
- Major Histocompatibility Complex (MHC) presents a challenge for the allogeneic MSC therapy as mismatch between the donor and recipient can lead to the rejection of the administered stem cells.
- The researchers aim to develop strategies to work around the immune rejection problem to enhance cell survival and the efficacy of allogeneic MSC therapy.
Research Objective and Methods
- The primary objective of the study was to investigate whether transforming growth factor-β2 (TGF-β2) could downregulate MHC expression on equine MSCs. Additionally, the study aimed to understand if TGF-β2 treatment affected the overall phenotype of the MSCs.
- MSCs derived from the bone marrow of twelve horses were treated with TGF-β2 at varying concentrations. These cells were then examined for changes in MHC I and MHC II surface expressions, morphology, viability, and TGF-β1 secretion.
Research Findings
- TGF-β2-treated MSCs showed reduced surface expression of both MHC I and MHC II, compared to untreated cells.
- TGF-β2 treatment was found to partially block the upregulation of MHC I and MHC II caused by the inflammatory stimulus IFN-γ.
- The effect of TGF-β2 was heavily dependent on the donor animal and the baseline expressions of MHC I and MHC II.
- TGF-β2 treatment did not appear to affect MSC morphology, surface marker expressions, cell viability, or TGF-β1 secretion.
- However, it did result in a notable increase in the number of cells obtained from culture.
Implications and Future Directions
- These findings suggest that TGF-β2 treatment has the potential to regulate MHC expressions on MSCs, aiding allogeneic therapies.
- More research is needed to ensure the stability of MHC expressions when an inflammatory stimulus is present.
Cite This Article
APA
Berglund AK, Fisher MB, Cameron KA, Poole EJ, Schnabel LV.
(2017).
Transforming Growth Factor-β2 Downregulates Major Histocompatibility Complex (MHC) I and MHC II Surface Expression on Equine Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Other Phenotypic Cell Surface Markers.
Front Vet Sci, 4, 84.
https://doi.org/10.3389/fvets.2017.00084 Publication
Researcher Affiliations
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
- Department of Biomedical Engineering, North Carolina State University, Raleigh, and University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States.
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States.
Grant Funding
- K08 AR060875 / NIAMS NIH HHS
References
This article includes 44 references
- Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RKW. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon.. Equine Vet J 2012 44:25–32.
- da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells.. Cytokine Growth Factor Rev 2009 20:419–27.
- Murphy KC, Fang SY, Leach JK. Human mesenchymal stem cell spheroids in fibrin hydrogels exhibit improved cell survival and potential for bone healing.. Cell Tissue Res 2014 357:91–9.
- Caplan AI, Sorrell JM. The MSC curtain that stops the immune system.. Immunol Lett 2015 168:136–9.
- Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection.. J Inflamm (Lond) 2005 2:8.
- Badillo AT, Beggs KJ, Javazon EH, Tebbets JC, Flake AW. Murine bone marrow stromal progenitor cells elicit an in vivo cellular and humoral alloimmune response.. Biol Blood Marrow Transplant 2007 13:412–22.
- Isakova IA, Lanclos C, Bruhn J, Kuroda MJ, Baker KC, Krishnappa V. Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo.. PLoS One 2014 9:e87238.
- Poncelet AJ, Vercruysse J, Saliez A, Gianello P. Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo.. Transplantation 2007 83:783–90.
- Eliopoulos N, Stagg J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice.. Gene Ther 2005 106:4057–65.
- Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells.. Stem Cells 2009 27:2865–74.
- Joswig A-J, Mitchell A, Cummings KJ, Levine GJ, Gregory CA, Smith R. Repeated intra-articular injection of allogeneic mesenchymal stem cells causes an adverse response compared to autologous cells in the equine model.. Stem Cell Res Ther 2017 8:42.
- Pezzanite LM, Fortier LA, Antczak DF, Cassano JM, Brosnahan MM, Miller D. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.. Stem Cell Res Ther 2015 6:1–11.
- Berglund AK, Schnabel LV. Allogeneic MHC-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-MHC antibodies.. Equine Vet J 2016 1–6.
- Halamay KE, Kirkman RL, Sun L, Yamada A, Fragoso RC, Shimizu K. CD8 T cells are sufficient to mediate allorecognition and allograft rejection.. Cell Immunol 2002 216:6–14.
- Steele DJ, Laufer TM, Smiley ST, Ando Y, Grusby MJ, Glimcher LH. Two levels of help for B cell alloantibody production.. J Exp Med 1996 183:699–703.
- Sauvé D, Baratin M, Leduc C, Bonin K, Daniel C. Alloantibody production is regulated by CD4+ T cells’ alloreactive pathway, rather than precursor frequency of Th1/Th2 differentiation.. Am J Transplant 2004 4:1237–45.
- Curry AJ, Pettigrew GJ, Negus MC, Easterfield AJ, Young JL, Bolton EM. Dendritic cells internalise and re-present conformationally intact soluble MHC class I alloantigen for generation of alloantibody.. Eur J Immunol 2007 37:696–705.
- Rinaldo CR. Modulation of major histocompatibility complex antigen expression by viral infection.. Am J Pathol 1994 144:637–50.
- Cromme FV, Walboomers JMM, Van Oostveen JW, Stukart MJ, De Gruijl TD, Kummer JA. Lack of granzyme expression in T lymphocytes indicates poor cytotoxic T lymphocyte activation in human papillomavirus-associated cervical carcinomas.. Int J Gynecol Cancer 1995 5:366–73.
- Niederkorn JY. Mechanisms of immune privilege in the eye and hair follicle.. J Investig Dermatol Symp Proc 2003 8:168–72.
- Siglienti I, Chan A, Kleinschnitz C, Jander S, Toyka KV, Gold R. Downregulation of transforming growth factor-beta2 facilitates inflammation in the central nervous system by reciprocal astrocyte/microglia interactions.. J Neuropathol Exp Neurol 2007 66:47–56.
- Ma D, Niederkorn JY. Transforming growth factor-beta down-regulates major histocompatibility complex class I antigen expression and increases the susceptibility of uveal melanoma cells to natural killer cell-mediated cytolysis.. Immunology 1995 86:263–9.
- Donnet-Hughes A, Schiffrin EJ, Huggett AC. Expression of MHC antigens by intestinal epithelial cells. Effect of transforming growth factor-beta 2 (TGF-beta 2).. Clin Exp Immunol 1995 99:240–4.
- Schluesener HJ. Transforming growth factors type beta 1 and beta 2 suppress rat astrocyte autoantigen presentation and antagonize hyperinduction of class II major histocompatibility complex antigen expression by interferon-gamma and tumor necrosis factor-alpha.. J Neuroimmunol 1990 27:41–7.
- Lee YJ, Han Y, Lu HT, Nguyen V, Qin H, Howe PH. TGF-beta suppresses IFN-gamma induction of class II MHC gene expression by inhibiting class II transactivator messenger RNA expression.. J Immunol 1997 158:2065–75.
- Schnabel LV, Pezzanite LM, Antczak DF, Felippe MJ, Fortier LA. Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro.. Stem Cell Res Ther 2014 5:13.
- Hill J, Cassano J, Goodale M, Fortier L. Mesenchymal stem cell antigenicity is supressed in an inflammed joint environment.. Am J Vet Res 2017 (in press).
- Radcliffe CH, Flaminio MJBF, Fortier LA. Temporal analysis of equine bone marrow aspirate during establishment of putative mesenchymal progenitor cell populations.. Stem Cells Dev 2010 19:269–82.
- Zuliani T, Saiagh S, Knol AC, Esbelin J, Dréno B. Fetal fibroblasts and keratinocytes with immunosuppressive properties for allogeneic cell-based wound therapy.. PLoS One 2013 8:e70408.
- Datto MB, Li Y, Panus JF, Howe DJ, Xiong Y, Wang XF. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism.. Proc Natl Acad Sci U S A 1995 92:5545–9.
- Moustakas A, Heldin CH. Non-Smad TGF-beta signals.. J Cell Sci 2005 118:3573–84.
- Carrade DD, Lame MW, Kent MS, Clark KC, Walker NJ, Borjesson DL. Comparative analysis of the immunomodulatory properties of equine adult-derived mesenchymal stem cells.. Cell Med 2012 4:1–11.
- Ljunggren HG, Kärre K. In search of the “missing self”: MHC molecules and NK cell recognition.. Immunol Today 1990 11:237–44.
- Hobbs CGL, Rees LEN, Heyderman RS, Birchall MA, Bailey M. Major histocompatibility complex class I expression in human tonsillar and laryngeal epithelium.. Clin Exp Immunol 2006 145:365–71.
- Chappell P, Meziane EK, Harrison M, Magiera L, Hermann C, Mears L. Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.. Elife 2015 2015:1–22.
- Lee K, Silva EA, Mooney DJ. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments.. J R Soc Interface 2011 8:153–70.
- Guo L, Zhou Y, Wang S, Wu Y. Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids.. J Cell Mol Med 2014 18:2009–19.
- Waldburger JM, Suter T, Fontana A, Acha-Orbea H, Reith W. Selective abrogation of major histocompatibility complex class II expression on extrahematopoietic cells in mice lacking promoter IV of the class II transactivator gene.. J Exp Med 2001 194:393–406.
- Moraes DA, Sibov TT, Pavon LF, Alvim PQ, Bonadio RS, Da Silva JR. A reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells.. Stem Cell Res Ther 2016 7:97.
- Grotendorst GR. Connective tissue growth factor: a mediator of TGf-β action on fibroblasts.. Cytokine Growth Factor Rev 1997 8:171–9.
- Kretlow JD, Jin Y-Q, Liu W, Zhang WJ, Hong T-H, Zhou G. Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells.. BMC Cell Biol 2008 9:60.
- Fafián-Labora J, Fernández-Pernas P, Fuentes I, De Toro J, Oreiro N, Sangiao-Alvarellos S. Influence of age on rat bone-marrow mesenchymal stem cells potential.. Sci Rep 2015 5:16765.
- Morikawa M, Koinuma D, Miyazono K, Heldin C-H. Genome-wide mechanisms of Smad binding.. Oncogene 2012 32:1–7.
- Watabe T, Miyazono K. Roles of TGF-β family signaling in stem cell renewal and differentiation TGF-β family signaling in the maintenance of pluripotency and self-renewal of embryonic stem (ES) cells.. Cell Res 2009 19323:103–15.
Citations
This article has been cited 28 times.Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
