Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome

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Abstract

Background

Adipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular, and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs, with an emphasis on their immunomodulatory capacity and transcriptome.

Methods

Human and feline ASCs were evaluated for phenotype, immunomodulatory profile, and transcriptome. Additionally, transwells were used to determine the role of cell-cell contact in ASC-mediated inhibition of lymphocyte proliferation in both humans and cats.

Results

Similar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity, and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen-activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern, including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta, and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of three unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis; 2) cell adhesion; 3) response to oxidative stress; and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs.

Conclusions

Findings suggest that feline ASCs modulate lymphocyte proliferation using soluble mediators that mirror the human ASC secretion pattern. Uninduced feline ASCs have similar gene expression profiles to uninduced human ASCs, as revealed by transcriptome analysis. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.

Electronic supplementary material

The online version of this article (doi:10.1186/s13287-017-0528-z) contains supplementary material, which is available to authorized users.

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Most cited references 36

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Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy.

Justin Glenn, Katharine A. Whartenby (2014)

Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.

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CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease.

Dainius Characiejus, Vita Pasukoniene, Marius Strioga (2011)

Chronic antigenic stimulation leads to gradual accumulation of late-differentiated, antigen-specific, oligoclonal T cells, particularly within the CD8(+) T-cell compartment. They are characterized by critically shortened telomeres, loss of CD28 and/or gain of CD57 expression and are defined as either CD8(+) CD28(-) or CD8(+) CD57(+) T lymphocytes. There is growing evidence that the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population plays a significant role in various diseases or conditions, associated with chronic immune activation such as cancer, chronic intracellular infections, chronic alcoholism, some chronic pulmonary diseases, autoimmune diseases, allogeneic transplantation, as well as has a great influence on age-related changes in the immune system status. CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population is heterogeneous and composed of various functionally competing (cytotoxic and immunosuppressive) subsets thus the overall effect of CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell-mediated immunity depends on the predominance of a particular subset. Many articles claim that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells have lost their proliferative capacity during process of replicative senescence triggered by repeated antigenic stimulation. However recent data indicate that CD8(+) CD28(-) (CD8(+) CD57(+)) T cells can transiently up-regulate telomerase activity and proliferate under certain stimulation conditions. Similarly, conflicting data is provided regarding CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell sensitivity to apoptosis, finally leading to the conclusion that this T-cell population is also heterogeneous in terms of its apoptotic potential. This review provides a comprehensive approach to the CD8(+) CD28(-) (CD8(+) CD57(+)) T-cell population: we describe in detail its origins, molecular and functional characteristics, subsets, role in various diseases or conditions, associated with persistent antigenic stimulation. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

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CD28 extinction in human T cells: altered functions and the program of T-cell senescence.

A. Londoño-Vallejo (2005)

The loss of CD28 expression on T cells is the most consistent biological indicator of aging in the human immune system, and the frequency of CD28(null) T cells is a key predictor of immune incompetence in the elderly. There is also mounting evidence for the high frequency of these unusual T cells among patients with inflammatory syndromes or with chronic infections disproportionate with their age. In these pathological states, CD28(null) T cells likely represent prematurely senescent lymphocytes due to persistent immune activation. Unlike the situation in CD28 gene knockout mice that have anergic CD28(0/0) T cells, human CD28(null) T cells are functionally active, long-lived, oligoclonal lymphocytes that lack or have limited proliferative capacity. Results of replicative senescence studies show that CD28(null) T cells are derived from CD28(+) precursors that have undergone repeated stimulation, indicating that CD28 silencing underlies the program of T-cell aging. Dissection of the machinery regulating CD28 expression is paving the way in elucidating the molecular events leading to immune senescence as well as providing clues into the functional rejuvenation of senescent T cells.

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Author and article information

Contributors

Kaitlin C. Clark: kcclark@ucdavis.edu

Fernando A. Fierro: ffierro@ucdavis.edu

Emily Mills Ko: ejmills@ucdavis.edu

Naomi J. Walker: njwalker@ucdavis.edu

Boaz Arzi: barzi@ucdavis.edu

Clifford G. Tepper: cgtepper@ucdavis.edu

Heather Dahlenburg: hrstewart@ucdavis.edu

Andrew Cicchetto: andrewcicchetto@gmail.com

Amir Kol: akol@ucdavis.edu

Lyndsey Marsh: ljmarsh@ucdavis.edu

William J. Murphy: wmjmurphy@ucdavis.edu

Nasim Fazel: nfazel@ucdavis.edu

Dori L. Borjesson: (530) 754-5202 , dlborjesson@ucdavis.edu

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 20 March 2017

Publication date PMC-release: 20 March 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 69

Affiliations

[1 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Veterinary Institute for Regenerative Cures and Department of Pathology, Microbiology and Immunology, , University of California, ; Davis, CA 95816 USA

[2 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Institute for Regenerative Cures and Department of Cell Biology and Human Anatomy, , University of California, ; Davis, CA 95816 USA

[3 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, , University of California, ; Davis, CA 95816 USA

[4 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Department of Biochemistry and Molecular Medicine, , University of California, ; Davis, CA 95816 USA

[5 ]ISNI 0000 0004 1936 9684, GRID grid.27860.3b, Department of Dermatology, School of Medicine, , University of California, ; Davis, CA 95816 USA

Article

Publisher ID: 528

DOI: 10.1186/s13287-017-0528-z

PMC ID: 5360077

PubMed ID: 28320483

SO-VID: a828c71c-3030-475c-ab07-38b956e8e793

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 November 2016

Date revision received : 10 February 2017

Date accepted : 3 March 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: 1R21DE024711-01

Award Recipient : Dori L. Borjesson

Funded by: California Institute for Regenerative Medicine (US)

Award ID: TB1-01184

Award Recipient : Kaitlin C. Clark

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: multipotent adult progenitor cell,mesenchymal stem cell,adipose tissue,feline,human,animal model,immunomodulation

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: multipotent adult progenitor cell, mesenchymal stem cell, adipose tissue, feline, human, animal model, immunomodulation

Human and feline adipose-derived mesenchymal stem cells have comparable phenotype, immunomodulatory functions, and transcriptome

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Genes & Diseases

Most cited references 36

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy.

CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease.

CD28 extinction in human T cells: altered functions and the program of T-cell senescence.

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