Abstract
Bone marrow–derived stromal cells or mesenchymal stromal cells (BMSCs or MSCs, as
we will call them in this work) are multipotent progenitor cells that can differentiate
into osteoblasts, adipocytes and chondrocytes. In addition, MSCs have been shown to
modulate the function of a variety of immune cells. Donor age has been shown to affect
the regenerative potential, differentiation, proliferation and anti-inflammatory potency
of MSCs; however, the impact of donor age on their immunosuppressive activity is unknown.
In this study, we evaluated the ability of MSCs derived from very young children and
adults on T-cell suppression and cytokine secretion by monocytes/macrophages. MSCs
were obtained from extra digits of children between 10 and 21 months and adults between
28 and 64 years of age. We studied cell surface marker expression, doubling time,
lineage differentiation potential and immunosuppressive function of the MSCs. Young
MSCs double more quickly and differentiate into bone and fat cells more efficiently
than those from older donors. They also form more and dense colonies of fibroblasts
(colony forming unit–fibroblast [CFU-F]). MSCs from both young and adult subjects
suppressed T-cell proliferation in a mitogen-induced assay at 1:3 and 1:30 ratios.
At a 1:30 ratio, however, MSCs from adults did not, but MSCs from infants did suppress
T-cell proliferation. In the mixed lymphocyte reaction assay, MSCs from infants produced
similar levels of suppression at all three MSC/T-cell ratios, but adult MSCs only
inhibited T-cell proliferation at a 1:3 ratio. Cytokine analyses of co-cultures of
MSCs and macrophages showed that both adult and young MSCs suppress tumor necrosis
factor alpha (TNF-α) and induce interleukin-10 (IL-10) production in macrophage co-culture
assay in a similar manner. Overall, this work shows that developing MSCs display a
higher level of immunosuppression than mature MSCs.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to CytotherapyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Functional heterogeneity of mesenchymal stem cells: implications for cell therapy.Journal of cellular biochemistry. 2012; 113: 2806-2812
- Mesenchymal stem cells: revisiting history, concepts, and assays.Cell stem cell. 2008; 2: 313-319
- Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.Blood. 2002; 99: 3838-3843
- Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lancet (London, England). 2004; 363: 1439-1441
- Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.Lancet (London, England). 2008; 371: 1579-1586
- Mesenchymal stem cells and immunomodulation: current status and future prospects.Cell death & disease. 2016; 7: e2062
- Immunomodulatory properties of mesenchymal stromal cells.Blood. 2007; 110: 3499-3506
- Bone marrow stromal cells as immunomodulators. A primer for dermatologists.J Dermatol Sci. 2015; 77: 11-20
- Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans.Stem cells (Dayton, Ohio). 2009; 27: 1421-1432
- Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy.Blood. 2005; 106: 1755-1761
- Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes.Journal of immunology (Baltimore, Md. : 1950). 2009; 183: 993-1004
- Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 5652-5657
- Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.Nature medicine. 2009; 15: 42-49
- Bone marrow-derived mesenchymal stem cells in repair of the injured lung.American journal of respiratory cell and molecular biology. 2005; 33: 145-152
- Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI:C-induced primary biliary cirrhosis mouse model.Clinical and experimental medicine. 2011; 11: 25-32
- Intravenous administration of bone marrow mesenchymal stem cells benefits experimental autoimmune myasthenia gravis mice through an immunomodulatory action.Scandinavian journal of immunology. 2010; 72: 242-249
- Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II.Stroke. 2011; 42: 825-829
- Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease.Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2009; 15: 804-811
- Treatment of refractory acute GVHD with third-party MSC expanded in platelet lysate-containing medium.Bone marrow transplantation. 2009; 43: 245-251
- Mesenchymal SCT ameliorates refractory cytopenia in patients with systemic lupus erythematosus.Bone marrow transplantation. 2013; 48: 544-550
- Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience.Cell transplantation. 2013; 22: 2267-2277
- Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.Archives of neurology. 2010; 67: 1187-1194
- Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study.The Lancet. Neurology. 2012; 11: 150-156
- Immunomodulatory properties of human placental mesenchymal stem/stromal cells.Placenta. 2017;
- Functional effects of TGF-beta1 on mesenchymal stem cell mobilization in cockroach allergen-induced asthma.Journal of immunology (Baltimore, Md.: 1950). 2014; 192: 4560-4570
- Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.Clinical and experimental immunology. 2007; 149: 353-363
- Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.Cell stem cell. 2008; 2: 141-150
- Mesenchymal Stem Cell-derived Extracellular Vesicles: Toward Cell-free Therapeutic Applications.Mol Ther. 2015; 23: 812-823
- MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease.Leukemia. 2014; 28: 970-973
- Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis.Cell and tissue research. 2018; 374: 1-15
- Treatment of inflammatory diseases with mesenchymal stem cells.Inflamm Allergy Drug Targets. 2009; 8: 110-123
- Mesenchymal stromal cells: sensors and switchers of inflammation.Cell stem cell. 2013; 13: 392-402
- MSCs-cells with many sides.Cytotherapy. 2018; 20: 273-278
- Equine mesenchymal stromal cells from different tissue sources display comparable immune-related gene expression profiles in response to interferon gamma (IFN)-gamma.Vet Immunol Immunopathol. 2018; 202: 25-30
- Immunosuppressive mechanisms of embryonic stem cells and mesenchymal stem cells in alloimmune response.Transplant immunology. 2011; 25: 7-15
- Mesenchymal stem cells. A potential source for skeletal repair.Annals of the rheumatic diseases. 2002; 61: ii29-ii31
- Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies.Mechanisms of ageing and development. 2008; 129: 163-173
- Intra-subject variability in human bone marrow stromal cell (BMSC) replicative senescence: molecular changes associated with BMSC senescence.Stem Cell Res. 2013; 11: 1060-1073
- Aging bone marrow mesenchymal stromal cells have altered membrane glycerophospholipid composition and functionality.Journal of lipid research. 2013; 54: 622-635
- A mesenchymal stromal cell gene signature for donor age.PLoS One. 2012; 7: e42908
- The establishment of a bank of stored clinical bone marrow stromal cell products.J Transl Med. 2012; 10: 23
- Comparative characterization of porcine mesenchymal stem cells derived from bone marrow extract and skin tissues.Tissue engineering. Part C, Methods. 2010; 16: 1481-1491
- Normalized median fluorescence: an alternative flow cytometry analysis method for tracking human embryonic stem cell states during differentiation.Tissue engineering. Part C, Methods. 2013; 19: 156-165
- Generation of rodent and human osteoblasts.BoneKEy reports. 2014; 3: 585
- Transglutaminase 2–a novel inhibitor of adipogenesis.Cell death & disease. 2015; 6: e1868
- Assessing the potential of colony morphology for dissecting the CFU-F population from human bone marrow stromal cells.Cell and tissue research. 2013; 352: 237-247
- Immunomodulatory effect of vitamin K2: Implications for bone health.Oral Dis. 2018; 24: 67-71
- A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance.Stem Cell Res Ther. 2015; 6: 236
- THP-1 cell line: an in vitro cell model for immune modulation approach.Int Immunopharmacol. 2014; 23: 37-45
- Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation.Nucleic Acids Res. 2012; 40: 4288-4297
- The START App: a web-based RNAseq analysis and visualization resource.Bioinformatics. 2017; 33: 447-449
- Comparison of Immunomodulation Properties of Porcine Mesenchymal Stromal/Stem Cells Derived from the Bone Marrow, Adipose Tissue, and Dermal Skin Tissue.Stem cells international. 2016; 20169581350
- Mesenchymal stem cells and infectious diseases: Smarter than drugs.Immunol Lett. 2015; 168: 208-214
- Stem Cells in Skin Wound Healing: Are We There Yet?.Advances in Wound Care. 2016; 5: 164-175
- The suppressive effect of mesenchymal stromal cells on T cell proliferation is conserved in old age.Transplant immunology. 2011; 25: 167-172
- Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages.Exp Hematol. 2009; 37: 1445-1453
- Similarities and differences between porcine mandibular and limb bone marrow mesenchymal stem cells.Arch Oral Biol. 2017; 77: 1-11
- Polydactyly: how many disorders and how many genes? 2010 update.Dev Dyn. 2011; 240: 931-942
- Mesenchymal stromal cells and the innate immune response.Immunol Lett. 2015; 168: 140-146
- Dynamic compaction of human mesenchymal stem/precursor cells into spheres self-activates caspase-dependent IL1 signaling to enhance secretion of modulators of inflammation and immunity (PGE2, TSG6, and STC1).Stem cells (Dayton, Ohio). 2013; 31: 2443-2456
- Data against a Common Assumption: Xenogeneic Mouse Models Can Be Used to Assay Suppression of Immunity by Human MSCs.Mol Ther. 2017; 25: 1748-1756
- TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo.Proceedings of the National Academy of Sciences of the United States of America. 2014; 111: 16766-16771
- Enriched protein screening of human bone marrow mesenchymal stromal cell secretions reveals MFAP5 and PENK as novel IL-10 modulators.Mol Ther. 2014; 22: 999-1007
- Characterization of new members of the pregnancy-specific beta 1-glycoprotein family.Mol Cell Biochem. 1991; 106: 161-170
- Characterization of cDNAs of the human pregnancy-specific beta 1-glycoprotein family, a new subfamily of the immunoglobulin gene superfamily.Biochemistry. 1990; 29: 2845-2852
- Adipose-tissue-derived and Wharton's jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor.Tissue Eng Part A. 2010; 16: 3537-3546
- Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.Sci Transl Med. 2017; 9
Article info
Publication history
Published online: December 27, 2018
Accepted:
November 29,
2018
Received:
June 28,
2018
Identification
Copyright
Published by Elsevier Inc. on behalf of International Society for Cell and Gene Therapy.
