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Biomedicines
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Mesenchymal Stromal Cells in Human Disease and Therapy
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Mesenchymal Stromal Cells in Human Disease and Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 8012

Special Issue Editors

Prof. Dr. Joaquim M. S. Cabral

E-Mail Website
Guest Editor
Department of Bioengineering and IBB - Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: human mesenchymal stromal cells (hMSCs); ex-vivo expansion, differentiation and purification of hMSC; bioreactors for hMSC manufacturing; process integration of upstream and downstream of hMSCs
Dr. Cláudia Lobato da Silva

E-Mail Website
Guest Editor
Department of Bioengineering and IBB - Institute of Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: bone marrow niche; expansion of human stem cells; cellular therapies with stem cells; bioreactors for stem cell culture and production of extracellular vesicles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the earliest clinical trials testing the infusion of mesenchymal stromal cells (MSCs) to improve the outcome of bone marrow transplantation, MSCs have been among the most exploited cell types in clinical trials. Owing to their availability from a wide range of tissue sources, high proliferative potential in vitro, multilineage differentiation capacity, trophic features and immunomodulatory properties, MSCs are considered promising therapeutic candidates for the treatment of a wide range of diseases. However, despite the great promise for MSC-based therapies, further research is needed to have a better understanding of the basic biology of these cells and their role in tissue regeneration/repair, as well as their participation in disease development.

In this Special Issue, we invite experts to share their research findings in topics related to (i) the mechanisms underlying the role of endogenous MSCs in disease initiation and progression; and to (ii) the therapeutic role of MSCs and/or their derived products such as extracellular vesicles, including but not limited to their hematopoietic supportive function, immunomodulatory capacity and regenerative abilities, as well as their potential for gene/drug delivery. We also expect contributions on the latest advances in the clinical translation of MSC-based therapies and how to address manufacturing challenges. 

Prof. Dr. Joaquim M. S. Cabral
Dr. Cláudia Lobato da Silva
Guest Editors

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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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.

Keywords

  • mesenchymal stromal cells (MSCs)
  • cellular therapy
  • bone marrow microenvironment
  • multilineage differentiation
  • trophic ability
  • immunomodulatory potential
  • extracellular vesicles
  • cell manufacturing

Published Papers (4 papers)

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Research

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35 pages, 13456 KiB  
Article
Umbilical-Cord-Derived Mesenchymal Stromal Cells Modulate 26 Out of 41 T Cell Subsets from Systemic Sclerosis Patients
by Paula Laranjeira, Francisco dos Santos, Maria João Salvador, Irina N. Simões, Carla M. P. Cardoso, Bárbara M. Silva, Helena Henriques-Antunes, Luísa Corte-Real, Sofia Couceiro, Filipa Monteiro, Carolina Santos, Tânia Santiago, José A. P. da Silva and Artur Paiva
Biomedicines 2023, 11(5), 1329; https://doi.org/10.3390/biomedicines11051329 - 30 Apr 2023
Cited by 2 | Viewed by 1843
Abstract
Systemic sclerosis (SSc) is an immune-mediated disease wherein T cells are particularly implicated, presenting a poor prognosis and limited therapeutic options. Thus, mesenchymal-stem/stromal-cell (MSC)-based therapies can be of great benefit to SSc patients given their immunomodulatory, anti-fibrotic, and pro-angiogenic potential, which is associated [...] Read more.
Systemic sclerosis (SSc) is an immune-mediated disease wherein T cells are particularly implicated, presenting a poor prognosis and limited therapeutic options. Thus, mesenchymal-stem/stromal-cell (MSC)-based therapies can be of great benefit to SSc patients given their immunomodulatory, anti-fibrotic, and pro-angiogenic potential, which is associated with low toxicity. In this study, peripheral blood mononuclear cells from healthy individuals (HC, n = 6) and SSc patients (n = 9) were co-cultured with MSCs in order to assess how MSCs affected the activation and polarization of 58 different T cell subsets, including Th1, Th17, and Treg. It was found that MSCs downregulated the activation of 26 out of the 41 T cell subsets identified within CD4+, CD8+, CD4+CD8+, CD4−CD8−, and γδ T cells in SSc patients (HC: 29/42) and affected the polarization of 13 out of 58 T cell subsets in SSc patients (HC: 22/64). Interestingly, SSc patients displayed some T cell subsets with an increased activation status and MSCs were able to downregulate all of them. This study provides a wide-ranging perspective of how MSCs affect T cells, including minor subsets. The ability to inhibit the activation and modulate the polarization of several T cell subsets, including those implicated in SSc’s pathogenesis, further supports the potential of MSC-based therapies to regulate T cells in a disease whose onset/development may be due to immune system’s malfunction. Full article
(This article belongs to the Special Issue Mesenchymal Stromal Cells in Human Disease and Therapy)
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18 pages, 2587 KiB  
Article
Neurodifferentiation and Neuroprotection Potential of Mesenchymal Stromal Cell-Derived Secretome Produced in Different Dynamic Systems
by Cláudia Raquel Marques, Miguel de Almeida Fuzeta, Raquel Medina dos Santos Cunha, Joana Pereira-Sousa, Deolinda Silva, Jonas Campos, Andreia Teixeira-Castro, Rui Amandi Sousa, Ana Fernandes-Platzgummer, Cláudia L. da Silva and António José Salgado
Biomedicines 2023, 11(5), 1240; https://doi.org/10.3390/biomedicines11051240 - 22 Apr 2023
Cited by 3 | Viewed by 1409
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta, leading to a loss of DA in the basal ganglia. The presence of aggregates of alpha-synuclein [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta, leading to a loss of DA in the basal ganglia. The presence of aggregates of alpha-synuclein (α-synuclein) is seen as the main contributor to the pathogenesis and progression of PD. Evidence suggests that the secretome of mesenchymal stromal cells (MSC) could be a potential cell-free therapy for PD. However, to accelerate the integration of this therapy in the clinical setting, there is still the need to develop a protocol for the large-scale production of secretome under good manufacturing practices (GMP) guidelines. Bioreactors have the capacity to produce large quantities of secretomes in a scalable manner, surpassing the limitations of planar static culture systems. However, few studies focused on the influence of the culture system used to expand MSC, on the secretome composition. In this work, we studied the capacity of the secretome produced by bone marrow-derived mesenchymal stromal cells (BMSC) expanded in a spinner flask (SP) and in a Vertical-Wheel™ bioreactor (VWBR) system, to induce neurodifferentiation of human neural progenitor cells (hNPCs) and to prevent dopaminergic neuron degeneration caused by the overexpression of α-synuclein in one Caenorhabditis elegans model of PD. Results showed that secretomes from both systems were able to induce neurodifferentiation, though the secretome produced in the SP system had a greater effect. Additionally, in the conditions of our study, only the secretome produced in SP had a neuroprotective potential. Lastly, the secretomes had different profiles regarding the presence and/or specific intensity of different molecules, namely, interleukin (IL)-6, IL-4, matrix metalloproteinase-2 (MMP2), and 3 (MMP3), tumor necrosis factor-beta (TNF-β), osteopontin, nerve growth factor beta (NGFβ), granulocyte colony-stimulating factor (GCSF), heparin-binding (HB) epithelial growth factor (EGF)-like growth factor (HB-EGF), and IL-13. Overall, our results suggest that the culture conditions might have influenced the secretory profiles of cultured cells and, consequently, the observed effects. Additional studies should further explore the effects that different culture systems have on the secretome potential of PD. Full article
(This article belongs to the Special Issue Mesenchymal Stromal Cells in Human Disease and Therapy)
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18 pages, 2210 KiB  
Article
Improved Protocol to Study Osteoblast and Adipocyte Differentiation Balance
by Ana Alonso-Pérez, María Guillán-Fresco, Eloi Franco-Trepat, Alberto Jorge-Mora, Miriam López-Fagúndez, Andrés Pazos-Pérez, Antía Crespo-Golmar, José R. Caeiro-Rey and Rodolfo Gómez
Biomedicines 2023, 11(1), 31; https://doi.org/10.3390/biomedicines11010031 - 22 Dec 2022
Cited by 1 | Viewed by 1682
Abstract
Adipogenesis-osteoblastogenesis balance-rupture is relevant in multiple diseases. Current human mesenchymal stem cells (hMSCs) in vitro differentiation models are expensive, and are hardly reproducible. Their scarcity and variability make an affordable and reliable method to study adipocyte-osteoblast-equilibrium difficult. Moreover, media composition has been inconstant [...] Read more.
Adipogenesis-osteoblastogenesis balance-rupture is relevant in multiple diseases. Current human mesenchymal stem cells (hMSCs) in vitro differentiation models are expensive, and are hardly reproducible. Their scarcity and variability make an affordable and reliable method to study adipocyte-osteoblast-equilibrium difficult. Moreover, media composition has been inconstant throughout the literature. Our aims were to compare improved differentiation lab-made media with consensus/commercial media, and to identify a cell-line to simultaneously evaluate both MSCs differentiations. Lab-made media were compared with consensus and commercial media in C3H10T1/2 and hMSC, respectively. Lab-made media were tested on aged women primary pre-osteoblast-like cells. To determine the optimum cell line, C3H10T1/2 and hMSC-TERT cells were differentiated to both cell fates. Differentiation processes were evaluated by adipocytic and osteoblastic gene-markers expression and staining. Lab-made media significantly increased consensus medium induction and overcame commercial media in hMSCs differentiation to adipocytes and osteoblasts. Pre-osteoblast-like cells only properly differentiate to adipocyte. Lab-made media promoted adipocyte gene-markers expression in C3H10T1/2 and hMSC-TERT, and osteoblast gene-markers in C3H10T1/2. Oil Red O and Alizarin Red staining supported these findings. Optimized lab-made media were better at differentiating MSCs compared to consensus/commercial media, and evidenced the adipogenic commitment of pre-osteoblast-like cells from aged-women. C3H10T1/2 is an optimum MSC line by which to study adipocyte-osteoblast differentiation balance. Full article
(This article belongs to the Special Issue Mesenchymal Stromal Cells in Human Disease and Therapy)
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Review

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30 pages, 3332 KiB  
Review
Bioengineered Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles as an Improved Drug Delivery System: Methods and Applications
by Cristiana Ulpiano, Cláudia L. da Silva and Gabriel A. Monteiro
Biomedicines 2023, 11(4), 1231; https://doi.org/10.3390/biomedicines11041231 - 21 Apr 2023
Cited by 3 | Viewed by 2601
Abstract
Extracellular vesicles (EVs) are cell-derived nano-sized lipid membranous structures that modulate cell–cell communication by transporting a variety of biologically active cellular components. The potential of EVs in delivering functional cargos to targeted cells, their capacity to cross biological barriers, as well as their [...] Read more.
Extracellular vesicles (EVs) are cell-derived nano-sized lipid membranous structures that modulate cell–cell communication by transporting a variety of biologically active cellular components. The potential of EVs in delivering functional cargos to targeted cells, their capacity to cross biological barriers, as well as their high modification flexibility, make them promising drug delivery vehicles for cell-free therapies. Mesenchymal stromal cells (MSCs) are known for their great paracrine trophic activity, which is largely sustained by the secretion of EVs. MSC-derived EVs (MSC-EVs) retain important features of the parental cells and can be bioengineered to improve their therapeutic payload and target specificity, demonstrating increased therapeutic potential in numerous pre-clinical animal models, including in the treatment of cancer and several degenerative diseases. Here, we review the fundamentals of EV biology and the bioengineering strategies currently available to maximize the therapeutic value of EVs, focusing on their cargo and surface manipulation. Then, a comprehensive overview of the methods and applications of bioengineered MSC-EVs is presented, while discussing the technical hurdles yet to be addressed before their clinical translation as therapeutic agents. Full article
(This article belongs to the Special Issue Mesenchymal Stromal Cells in Human Disease and Therapy)
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