Functional aligned mesenchymal stem cell sheets fabricated using micropatterned thermo-responsive cell culture surfaces

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Abstract

Mesenchymal stem cells (MSCs) are frequently applied for cell transplantation and regenerative therapy because they secrete diverse therapeutic cytokines that prompt immuno-stimulatory and tissue repair processes. Furthermore, cultured MSC sheets exhibit enhanced cytokine secretion compared to their MSC suspensions, and represent a durable, versatile format for tissue engineering as singular, multi-layered, or multi-cell type sandwiched, transplantable constructs. Tissue engineered implants with various cellular orientations have been reported. In this study, patterned, temperature-responsive culture surfaces were used to prepare oriented MSC sheets. Patterned culture surfaces were fabricated by grafting polyacrylamide (PAAm) onto commercial poly( N-isopropylacrylamide) (PNIPAAm)-modified plastic via photopolymerization using a stripe-patterned photomask. Patterned surfaces were characterized using x-ray photoelectron spectroscopy, fluorescently labelled fibronectin and albumin adsorption assays, wetting (contact angle) measurements, atomic force microscopy, and scanning electron microscopy. Striped grafted patterns of PAAm were fabricated on the PNIPAAm-coated culture substrates, and PAAm polymerized within the PNIPAAm overlayer. Cell-aligned MSC sheets were then produced from MSC culture on this patterned surface, secreting higher amounts of therapeutic cytokines (vascular endothelial growth factor, hepatocyte growth factor, and transforming growth factor-β) than non-aligned MSC control sheets. In addition, aligned MSC sheets maintained enhanced cell multi-potent differentiation capabilities. New, aligned MSC sheets might exhibit improved functional properties for cell sheet transplant therapies.

Graphical abstract

Highlights

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Stripe patterned culture surfaces were fabricated via photopolymerization.
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Patterned culture dish fabricates aligned mesenchymal stem cell sheet.
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Aligned mesenchymal stem cell sheet secrets higher amounts of therapeutic cytokines.
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The stem cell sheet would be applicable for effective cell sheet transplant therapies.

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Most cited references 91

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Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [T(H)1] and T(H)2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor alpha (TNF-alpha) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused T(H)1 cells to decrease interferon gamma (IFN-gamma) and caused the T(H)2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (T(Regs)) present; and hMSCs decreased secretion of IFN-gamma from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE(2)) in co-cultures, and inhibitors of PGE(2) production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation.

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Is Open Access

Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs

Andreas Weiss, Marc Hendrik Dahlke (2019)

Expectations on mesenchymal stem cell (MSC) treatment are high, especially in the fields of sepsis, transplant medicine, and autoimmune diseases. Various pre-clinical studies have been conducted with encouraging results, although the mechanisms of action behind the observed immunomodulatory capacity of mesenchymal stem cells have not been fully understood. Previous studies have demonstrated that the immunomodulatory effect of MSCs is communicated via MSC-secreted cytokines and has been proven to rely on the local microenvironment as some of the observed effects depend on a pre-treatment of MSCs with inflammatory cytokines. Nonetheless, recent findings indicate that the cytokine-mediated effects are only one part of the equation as apoptotic, metabolically inactivated, or even fragmented MSCs have been shown to possess an immunomodulatory potential as well. Both cytokine-dependent and cytokine-independent mechanisms suggest a key role for regulatory T cells and monocytes in the overall pattern, but the principle as to why viable and non-viable MSCs have similar immunomodulatory capacities remains elusive. Here we review the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation and focus on the viability of MSCs, as there is still uncertainty concerning the tumorigenic potential of living MSCs.

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Author and article information

Contributors

Kenichi Nagase

Hironobu Takahashi

Journal

Journal ID (nlm-ta): Mater Today Bio

Journal ID (iso-abbrev): Mater Today Bio

Title: Materials Today Bio

Publisher: Elsevier

ISSN (Electronic): 2590-0064

Publication date PMC-release: 10 March 2025

Publication date Collection: June 2025

Publication date (Electronic): 10 March 2025

Volume: 32

Electronic Location Identifier: 101657

Affiliations

[a ]Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan

[b ]Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo, 105-8512, Japan

[c ]Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, 84112, USA

[d ]Cell Sheet Tissue Engineering Center (CSTEC), Department of Molecular Pharmaceutics, University of Utah, Health Sciences, Salt Lake City, UT, 84112, USA

[e ]Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan

Author notes

[* ]Corresponding author. Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima, 734-8553, Japan. nagase@ 123456hiroshima-u.ac.jp

[** ]Corresponding author. Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan. takahashi.hironobu@ 123456twmu.ac.jp

Article

Publisher Item ID: S2590-0064(25)00215-7 Publisher ID: 101657

DOI: 10.1016/j.mtbio.2025.101657

PMC ID: 11957804

PubMed ID: 40166377

SO-VID: 255f5c27-178d-441c-9a51-bc8ea72d696a

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 23 December 2024

Date revision received : 9 March 2025

Date accepted : 10 March 2025

Functional aligned mesenchymal stem cell sheets fabricated using micropatterned thermo-responsive cell culture surfaces

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