Microencapsulated equine mesenchymal stromal cells promote cutaneous wound healing in vitro

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Abstract

Introduction

The prevalence of impaired cutaneous wound healing is high and treatment is difficult and often ineffective, leading to negative social and economic impacts for our society. Innovative treatments to improve cutaneous wound healing by promoting complete tissue regeneration are therefore urgently needed. Mesenchymal stromal cells (MSCs) have been reported to provide paracrine signals that promote wound healing, but (i) how they exert their effects on target cells is unclear and (ii) a suitable delivery system to supply these MSC-derived secreted factors in a controlled and safe way is unavailable. The present study was designed to provide answers to these questions by using the horse as a translational model. Specifically, we aimed to (i) evaluate the in vitro effects of equine MSC-derived conditioned medium (CM), containing all factors secreted by MSCs, on equine dermal fibroblasts, a cell type critical for successful wound healing, and (ii) explore the potential of microencapsulated equine MSCs to deliver CM to wounded cells in vitro.

Methods

MSCs were isolated from the peripheral blood of healthy horses. Equine dermal fibroblasts from the NBL-6 (horse dermal fibroblast cell) line were wounded in vitro, and cell migration and expression levels of genes involved in wound healing were evaluated after treatment with MSC-CM or NBL-6-CM. These assays were repeated by using the CM collected from MSCs encapsulated in core-shell hydrogel microcapsules.

Results

Our salient findings were that equine MSC-derived CM stimulated the migration of equine dermal fibroblasts and increased their expression level of genes that positively contribute to wound healing. In addition, we found that equine MSCs packaged in core-shell hydrogel microcapsules had similar effects on equine dermal fibroblast migration and gene expression, indicating that microencapsulation of MSCs does not interfere with the release of bioactive factors.

Conclusions

Our results demonstrate that the use of CM from MSCs might be a promising new therapy for impaired cutaneous wounds and that encapsulation may be a suitable way to effectively deliver CM to wounded cells in vivo.

Electronic supplementary material

The online version of this article (doi:10.1186/s13287-015-0037-x) contains supplementary material, which is available to authorized users.

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Most cited references 45

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A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods

Marialaura Madrigal, Kosagisharaf Rao, Neil H Riordan (2014)

The mesenchymal stem cell (MSC) is being broadly studied in clinical trials. Contrary to the early paradigm of cell replacement and differentiation as a therapeutic mechanism of action, evidence is mounting that the secretions of the cells are responsible for their therapeutic effects. These secretions include molecules and extracellular vesicles that have both local and distant effects. This review summarizes the up- and down-regulation of MSC anti-inflammatory, immune modulating, anti-tumor, and regenerative secretions resulting from different stimuli including: a) hypoxia, which increases the production of growth factors and anti-inflammatory molecules; b) pro-inflammatory stimuli that induce the secretion of immune modulating and anti-inflammatory factors; and c) 3 dimensional growth which up regulates the production of anti-cancer factors and anti-inflammatory molecules compared to monolayer culture. Finally we review in detail the most important factors present in conditioned medium of MSC that can be considered protagonists of MSC physiological effects including HGF, TGF-b, VEGF, TSG-6, PGE2 and galectins 1, and 9. We conclude that there is potential for the development of acellular therapeutic interventions for autoimmune, inflammatory, and malignant diseases and tissue regeneration from cellular secretions derived from MSCs cultured under the appropriate conditions.

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Matrix metalloproteinases and their inhibitors in connective tissue remodeling.

J F WOESSNER (1991)

Matrix metalloproteinases are an important group of zinc enzymes responsible for degradation of the extracellular matrix components such as collagen and proteoglycans in normal embryogenesis and remodeling and in many disease processes such as arthritis, cancer, periodontitis, and osteoporosis. A matrixin family is defined, comprising at least seven members that range in size from Mr 28,000 to 92,000 and are related in gene sequence to collagenase. All family members are secreted as zymogens that lose peptides of about 10,000 daltons upon activation. Latency is due to a conserved cysteine that binds to zinc at the active center. Latency is overcome by physical (chaotropic agents), chemical (HOCl, mercurials), and enzymatic (trypsin, plasmin) treatments that separate the cysteine residue from the zinc. Expression of the metalloproteinases is switched on by a variety of agents acting through regulatory elements of the gene, particularly the AP-1 binding site. A family of protein inhibitors of Mr 28,500 or less binds strongly and stoichiometrically in noncovalent fashion to inhibit members of the family. The serum protein alpha 2-macroglobulin and relatives are also strongly inhibitory.

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Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells

Georg Siegel, Torsten Kluba, Ursula Hermanutz-Klein … (2013)

Background Mesenchymal stromal cells (MSCs) are attractive for cell-based therapies ranging from regenerative medicine and tissue engineering to immunomodulation. However, clinical efficacy is variable and it is unclear how the phenotypes defining bone marrow (BM)-derived MSCs as well as donor characteristics affect their functional properties. Methods BM-MSCs were isolated from 53 (25 female, 28 male; age: 13 to 80 years) donors and analyzed by: (1) phenotype using flow cytometry and cell size measurement; (2) in vitro growth kinetics using population doubling time; (3) colony formation capacity and telomerase activity; and (4) function by in vitro differentiation capacity, suppression of T cell proliferation, cytokines and trophic factors secretion, and hormone and growth factor receptor expression. Additionally, expression of Oct4, Nanog, Prdm14 and SOX2 mRNA was compared to pluripotent stem cells. Results BM-MSCs from younger donors showed increased expression of MCAM, VCAM-1, ALCAM, PDGFRβ, PDL-1, Thy1 and CD71, and led to lower IL-6 production when co-cultured with activated T cells. Female BM-MSCs showed increased expression of IFN-γR1 and IL-6β, and were more potent in T cell proliferation suppression. High-clonogenic BM-MSCs were smaller, divided more rapidly and were more frequent in BM-MSC preparations from younger female donors. CD10, β1integrin, HCAM, CD71, VCAM-1, IFN-γR1, MCAM, ALCAM, LNGFR and HLA ABC were correlated to BM-MSC preparations with high clonogenic potential and expression of IFN-γR1, MCAM and HLA ABC was associated with rapid growth of BM-MSCs. The mesodermal differentiation capacity of BM-MSCs was unaffected by donor age or gender but was affected by phenotype (CD10, IFN-γR1, GD2). BM-MSCs from female and male donors expressed androgen receptor and FGFR3, and secreted VEGF-A, HGF, LIF, Angiopoietin-1, basic fibroblast growth factor (bFGF) and NGFB. HGF secretion correlated negatively to the expression of CD71, CD140b and Galectin 1. The expression of Oct4, Nanog and Prdm14 mRNA in BM-MSCs was much lower compared to pluripotent stem cells and was not related to donor age or gender. Prdm14 mRNA expression correlated positively to the clonogenic potential of BM-MSCs. Conclusions By identifying donor-related effects and assigning phenotypes of BM-MSC preparations to functional properties, we provide useful tools for assay development and production for clinical applications of BM-MSC preparations.

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Author and article information

Contributors

Leen Bussche: lb548@cornell.edu

Rebecca M Harman: rmh12@cornell.edu

Bethany A Syracuse: bas346@cornell.edu

Eric L Plante: eric.plante@cortland.edu

Yen-Chun Lu: yl2347@cornell.edu

Theresa M Curtis: theresa.curtis@cortland.edu

Minglin Ma: mm826@cornell.edu

Gerlinde R Van de Walle: grv23@cornell.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): 11 April 2015

Publication date PMC-release: 11 April 2015

Publication date Collection: 2015

Volume: 6

Issue: 1

Electronic Location Identifier: 66

Affiliations

[ ]Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 235 Hungerford Hill Road, Ithaca, NY 14850 USA

[ ]Department of Biological Sciences, State University of New York at Cortland, 21 Graham Avenue, Cortland, NY 13045 USA

[ ]Department of Biological and Environmental Engineering, Cornell University, Wing Road, Ithaca, NY 14850 USA

Article

Publisher ID: 37

DOI: 10.1186/s13287-015-0037-x

PMC ID: 4413990

PubMed ID: 25889766

SO-VID: 2fcbc4a3-124e-4f3c-a632-2b0880f45ce9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 : 9 January 2015

Date revision received : 25 February 2015

Date accepted : 4 March 2015

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ScienceOpen disciplines: Molecular medicine

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Microencapsulated equine mesenchymal stromal cells promote cutaneous wound healing in vitro

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Abstract

Introduction

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Most cited references 45

A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods

Matrix metalloproteinases and their inhibitors in connective tissue remodeling.

Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells

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Cited by 25

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