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Cells
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Stromal Cells—Structure, Function and Therapeutics Development
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Stromal Cells—Structure, Function and Therapeutics Development

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 10458

Special Issue Editor

Prof. Dr. Veronika Lukacs-Kornek

E-Mail Website
Guest Editor
Institute of Experimental Immunology, University Clinic of Rheinische Friedrich-Wilhelms-University, Bonn, Germany
Interests: stromal cell

Special Issue Information

Dear Colleagues,

Stromal cells are the connective tissue cells of any organ and play a fundamental role in health and disease.

In recent years, we have made tangible progress in our understanding of stromal cell biology. Stromal cells' phenotype and function are dependent on the specific tissue microenvironment; at the same time, they could shape the organization, integrity, and dynamics of their microenvironment. The structure of stromal cells and their functions in different biological processes has attracted more and more research interest, such as for tissue development, immune responses, cancer, and other pathologies. Furthermore, stromal cells are also increasingly used as therapeutic tools, including in the fields of gene therapy,  translational tissue engineering, and regenerative medicine.

We welcome original manuscripts and reviews on any of the aforementioned aspects of stromal cell biology. 

Prof. Dr. Veronika Lukacs-Kornek
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

17 pages, 4244 KiB  
Article
Microtissue Culture Provides Clarity on the Relative Chondrogenic and Hypertrophic Response of Bone-Marrow-Derived Stromal Cells to TGF-β1, BMP-2, and GDF-5
by Rose Ann G. Franco, Eamonn McKenna, Md. Shafiullah Shajib, Bianca Guillesser, Pamela G. Robey, Ross W. Crawford, Michael R. Doran and Kathryn Futrega
Cells 2024, 13(1), 37; https://doi.org/10.3390/cells13010037 - 23 Dec 2023
Viewed by 1072
Abstract
Chondrogenic induction of bone-marrow-derived stromal cells (BMSCs) is typically accomplished with medium supplemented with growth factors (GF) from the transforming growth factor-beta (TGF-β)/bone morphogenetic factor (BMP) superfamily. In a previous study, we demonstrated that brief (1–3 days) stimulation with TGF-β1 was sufficient to [...] Read more.
Chondrogenic induction of bone-marrow-derived stromal cells (BMSCs) is typically accomplished with medium supplemented with growth factors (GF) from the transforming growth factor-beta (TGF-β)/bone morphogenetic factor (BMP) superfamily. In a previous study, we demonstrated that brief (1–3 days) stimulation with TGF-β1 was sufficient to drive chondrogenesis and hypertrophy using small-diameter microtissues generated from 5000 BMSC each. This biology is obfuscated in typical large-diameter pellet cultures, which suffer radial heterogeneity. Here, we investigated if brief stimulation (2 days) of BMSC microtissues with BMP-2 (100 ng/mL) or growth/differentiation factor (GDF-5, 100 ng/mL) was also sufficient to induce chondrogenic differentiation, in a manner comparable to TGF-β1 (10 ng/mL). Like TGF-β1, BMP-2 and GDF-5 are reported to stimulate chondrogenic differentiation of BMSCs, but the effects of transient or brief use in culture have not been explored. Hypertrophy is an unwanted outcome in BMSC chondrogenic differentiation that renders engineered tissues unsuitable for use in clinical cartilage repair. Using three BMSC donors, we observed that all GFs facilitated chondrogenesis, although the efficiency and the necessary duration of stimulation differed. Microtissues treated with 2 days or 14 days of TGF-β1 were both superior at producing extracellular matrix and expression of chondrogenic gene markers compared to BMP-2 and GDF-5 with the same exposure times. Hypertrophic markers increased proportionally with chondrogenic differentiation, suggesting that these processes are intertwined for all three GFs. The rapid action, or “temporal potency”, of these GFs to induce BMSC chondrogenesis was found to be as follows: TGF-β1 > BMP-2 > GDF-5. Whether briefly or continuously supplied in culture, TGF-β1 was the most potent GF for inducing chondrogenesis in BMSCs. Full article
(This article belongs to the Special Issue Stromal Cells—Structure, Function and Therapeutics Development)
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16 pages, 9197 KiB  
Article
Therapeutic Effects and Underlying Mechanism of SOCS-com Gene-Transfected ADMSCs in Pressure Ulcer Mouse Models
by Youngsic Eom, So Young Eom, Jeonghwa Lee, Saeyeon Hwang, Jihee Won, Hyunsoo Kim, Seok Chung, Hye Joung Kim and Mi-Young Lee
Cells 2023, 12(14), 1840; https://doi.org/10.3390/cells12141840 - 13 Jul 2023
Cited by 1 | Viewed by 1555
Abstract
Although the proportion of ulcer patients with medical problems among the elderly has increased with the extension of human life expectancy, treatment efficiency is drastically low, incurring substantial social costs. MSCs have independent regeneration potential, making them useful in clinical trials of difficult-to-treat [...] Read more.
Although the proportion of ulcer patients with medical problems among the elderly has increased with the extension of human life expectancy, treatment efficiency is drastically low, incurring substantial social costs. MSCs have independent regeneration potential, making them useful in clinical trials of difficult-to-treat diseases. In particular, ADMSCs are promising in the stem cell therapy industry as they can be obtained in vast amounts using non-invasive methods. Furthermore, studies are underway to enhance the regeneration potential of ADMSCs using cytokines, growth factors, and gene delivery to generate highly functional ADMSCs. In this study, key regulators of wound healing, SOCS-1, -3, and -5, were combined to maximize the regenerative potential of ADMSCs in pressure ulcer treatments. After transfecting SOCS-1, -3, -5, and SOCS-com into ADMSCs using a non-viral method, the expression of the inflammatory factors TNF-alpha, INF-gamma, and IL-10 was confirmed. ADMSCs transfected with SOCS-com showed decreased overall expression of inflammatory factors and increased expression of anti-inflammatory factors. Based on these results, we implanted ADMSCs transfected with SOCS-com into a pressure ulcer mouse model to observe their subsequent wound-healing effects. Notably, SOCS-com improved wound closure in ulcers, and reconstruction of the epidermis and dermis was observed. The healing mechanism of ADMSCs transfected with SOCS-com was examined by RNA sequencing. Gene analysis results confirmed that expression changes occurred in genes of key regulators of wound healing, such as chemokines, MMP-1, 9, CSF-2, and IL-33, and that such genetic changes enhanced wound healing in ulcers. Based on these results, we demonstrate the potential of ADMSCs transfected with SOCS-com as an ulcer treatment tool. Full article
(This article belongs to the Special Issue Stromal Cells—Structure, Function and Therapeutics Development)
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16 pages, 546 KiB  
Article
Drug Regulatory-Compliant Validation of a qPCR Assay for Bioanalysis Studies of a Cell Therapy Product with a Special Focus on Matrix Interferences in a Wide Range of Organ Tissues
by Hannes M. Schröder, Elke Niebergall-Roth, Alexandra Norrick, Jasmina Esterlechner, Christoph Ganss, Markus H. Frank and Mark A. Kluth
Cells 2023, 12(13), 1788; https://doi.org/10.3390/cells12131788 - 05 Jul 2023
Cited by 1 | Viewed by 1789
Abstract
Quantitative polymerase chain reaction (qPCR) has emerged as an important bioanalytical method for assessing the pharmacokinetics of human-cell-based medicinal products after xenotransplantation into immunodeficient mice. A particular challenge in bioanalytical qPCR studies is that the different tissues of the host organism can affect [...] Read more.
Quantitative polymerase chain reaction (qPCR) has emerged as an important bioanalytical method for assessing the pharmacokinetics of human-cell-based medicinal products after xenotransplantation into immunodeficient mice. A particular challenge in bioanalytical qPCR studies is that the different tissues of the host organism can affect amplification efficiency and amplicon detection to varying degrees, and ignoring these matrix effects can easily cause a significant underestimation of the true number of target cells in a sample. Here, we describe the development and drug regulatory-compliant validation of a TaqMan® qPCR assay for the quantification of mesenchymal stromal cells in the range of 125 to 20,000 cells/200 µL lysate via the amplification of a human-specific, highly repetitive α-satellite DNA sequence of the chromosome 17 centromere region HSSATA17. An assessment of matrix effects in 14 different mouse tissues and blood revealed a wide range of spike recovery rates across the different tissue types, from 11 to 174%. Based on these observations, we propose performing systematic spike-and-recovery experiments during assay validation and correcting for the effects of the different tissue matrices on cell quantification in subsequent bioanalytical studies by multiplying the back-calculated cell number by tissue-specific factors derived from the inverse of the validated percent recovery rate. Full article
(This article belongs to the Special Issue Stromal Cells—Structure, Function and Therapeutics Development)
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10 pages, 1352 KiB  
Communication
Kinetics of Wound Development and Healing Suggests a Skin-Stabilizing Effect of Allogeneic ABCB5+ Mesenchymal Stromal Cell Treatment in Recessive Dystrophic Epidermolysis Bullosa
by Elke Niebergall-Roth, Kathrin Dieter, Cristina Daniele, Silvia Fluhr, Maria Khokhrina, Ines Silva, Christoph Ganss, Markus H. Frank and Mark A. Kluth
Cells 2023, 12(11), 1468; https://doi.org/10.3390/cells12111468 - 24 May 2023
Cited by 2 | Viewed by 3100
Abstract
Recessive dystrophic epidermolysis (RDEB) is a rare, inherited, and currently incurable skin blistering disorder characterized by cyclically recurring wounds coexisting with chronic non-healing wounds. In a recent clinical trial, three intravenous infusions of skin-derived ABCB5+ mesenchymal stromal cells (MSCs) to 14 patients [...] Read more.
Recessive dystrophic epidermolysis (RDEB) is a rare, inherited, and currently incurable skin blistering disorder characterized by cyclically recurring wounds coexisting with chronic non-healing wounds. In a recent clinical trial, three intravenous infusions of skin-derived ABCB5+ mesenchymal stromal cells (MSCs) to 14 patients with RDEB improved the healing of wounds that were present at baseline. Since in RDEB even minor mechanical forces perpetually provoke the development of new or recurrent wounds, a post-hoc analysis of patient photographs was performed to specifically assess the effects of ABCB5+ MSCs on new or recurrent wounds by evaluating 174 wounds that occurred after baseline. During 12 weeks of systemic treatment with ABCB5+ MSCs, the number of newly occurring wounds declined. When compared to the previously reported healing responses of the wounds present at baseline, the newly occurring wounds healed faster, and a greater portion of healed wounds remained stably closed. These data suggest a previously undescribed skin-stabilizing effect of treatment with ABCB5+ MSCs and support repeated dosing of ABCB5+ MSCs in RDEB to continuously slow the wound development and accelerate the healing of new or recurrent wounds before they become infected or progress to a chronic, difficult-to-heal stage. Full article
(This article belongs to the Special Issue Stromal Cells—Structure, Function and Therapeutics Development)
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24 pages, 4146 KiB  
Article
Mesenchymal Stem/Stromal Cells Derived from Cervical Cancer Promote M2 Macrophage Polarization
by Víctor Adrián Cortés-Morales, Luis Chávez-Sánchez, Leticia Rocha-Zavaleta, Sandra Espíndola-Garibay, Alberto Monroy-García, Marta Elena Castro-Manrreza, Guadalupe Rosario Fajardo-Orduña, Teresa Apresa-García, Marcos Gutiérrez-de la Barrera, Héctor Mayani and Juan José Montesinos
Cells 2023, 12(7), 1047; https://doi.org/10.3390/cells12071047 - 30 Mar 2023
Cited by 6 | Viewed by 2349
Abstract
Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage [...] Read more.
Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity. Full article
(This article belongs to the Special Issue Stromal Cells—Structure, Function and Therapeutics Development)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Production of extracellular vesicels with MSCs using stirred tank bioreactor and chemically defined medium
Authors: Barekzai, Jan; Friedrich Jonas; Pfening, Viktoria; Salzig, Denise
Affiliation: /
Abstract: /

Title: The Role of Mesenchymal Stomal Cells in Head and Neck Cancer Microenvironment - Their Regulatory Mechanisms of Pro- and Anti-Cancer Activity, Their Use in MSC-based Treatments and Future Clinical Challenges
Authors: Katarzyna Starska-Kowarska
Affiliation: Department of Physiology, Pathophysiology and Clinical Immunology Medical University of Lodz, Zeligowskiego 7/9, Lodz, Poland
Abstract: /

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