Research

Jump to: Review

16 pages, 4383 KiB

Open AccessArticle

In Vivo Evaluation of Mechanically Processed Stromal Vascular Fraction in a Chamber Vascularized by an Arteriovenous Shunt

by Bong-Sung Kim, Shih-Heng Chen, Mauro Vasella, Marco Guidi, Epameinondas Gousopoulos, Nicole Lindenblatt and Huang-Kai Kao

Pharmaceutics 2022, 14(2), 417; https://doi.org/10.3390/pharmaceutics14020417 - 14 Feb 2022

Cited by 4 | Viewed by 2197

Abstract

Mechanically processed stromal vascular fraction (mSVF) is a promising source for regenerative purposes. To study the in vivo fate of the mSVF, we herein used a vascularized tissue engineering chamber that insulates the target mSVF from the surrounding environment. In contrast to previous [...] Read more.

Mechanically processed stromal vascular fraction (mSVF) is a promising source for regenerative purposes. To study the in vivo fate of the mSVF, we herein used a vascularized tissue engineering chamber that insulates the target mSVF from the surrounding environment. In contrast to previous models, we propose an arteriovenous (AV) shunt between saphenous vessels in rats without a venous graft. Mechanical SVF was processed from the fat pads of male Sprague Dawley rats, mixed with a fibrin hydrogel and implanted into an inguinal tissue engineering chamber. An arteriovenous shunt was established between saphenous artery and vein. On the contralateral side, an mSVF-fibrin hydrogel mix without vascular axis served as a non-vascularized control. After two and six weeks, rats were sacrificed for further analysis. Mechanical SVF showed significant numbers of mesenchymal stromal cells. Vascularized mSVF explants gained weight over time. Perilipin and CD31 expression were significantly higher in the mSVF explants after six weeks while no difference in DAPI positive cells, collagen deposition and FABP4 expression was observed. Morphologically, no differentiated adipocytes but a dense cell-rich tissue with perilipin-positive cells was found after six weeks. The phosphorylation of ERK1/2 was significantly enhanced after six weeks while Akt activation remained unaltered. Finally, mSVF explants stably expressed and released VEGF, bFGF and TGFb. Vascularized mSVF is able to proliferate and express adipocyte-specific markers. The AV shunt model is a valuable refinement of currently existing AV loop models in the rat which contributes to the fundamental 3R principles of animal research. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

26 pages, 3860 KiB

Open AccessArticle

Human Bone Marrow Mesenchymal Stromal/Stem Cells Regulate the Proinflammatory Response of Monocytes and Myeloid Dendritic Cells from Patients with Rheumatoid Arthritis

by Paula Laranjeira, Mónia Pedrosa, Cátia Duarte, Susana Pedreiro, Brígida Antunes, Tânia Ribeiro, Francisco dos Santos, António Martinho, Margarida Fardilha, M. Rosário Domingues, Manuel Abecasis, José António Pereira da Silva and Artur Paiva

Pharmaceutics 2022, 14(2), 404; https://doi.org/10.3390/pharmaceutics14020404 - 12 Feb 2022

Cited by 6 | Viewed by 2471

Abstract

Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human [...] Read more.

Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Graphical abstract

15 pages, 4633 KiB

Open AccessArticle

MSC Secretome as a Promising Tool for Neuroprotection and Neuroregeneration in a Model of Intracerebral Hemorrhage

by Maxim Karagyaur, Stalik Dzhauari, Nataliya Basalova, Natalia Aleksandrushkina, Georgy Sagaradze, Natalia Danilova, Pavel Malkov, Vladimir Popov, Mariya Skryabina, Anastasia Efimenko and Vsevolod Tkachuk

Pharmaceutics 2021, 13(12), 2031; https://doi.org/10.3390/pharmaceutics13122031 - 29 Nov 2021

Cited by 10 | Viewed by 2313

Abstract

Multipotent mesenchymal stromal cells (MSCs) are considered to be critical contributors to injured tissue repair and regeneration, and MSC-based therapeutic approaches have been applied to many peripheral and central neurologic disorders. It has been demonstrated that the beneficial effects of MSC are mainly [...] Read more.

Multipotent mesenchymal stromal cells (MSCs) are considered to be critical contributors to injured tissue repair and regeneration, and MSC-based therapeutic approaches have been applied to many peripheral and central neurologic disorders. It has been demonstrated that the beneficial effects of MSC are mainly mediated by the components of their secretome. In the current study, we have explored the neuroprotective potential of the MSC secretome in a rat model of intracerebral hemorrhage and shown that a 10-fold concentrated secretome of human MSC and its combination with the brain-derived neurotrophic factor (BDNF) provided a better survival and neurological outcome of rats within 14 days of intracerebral hemorrhage compared to the negative (non-treated) and positive (BDNF) control groups. We found that it was due to the ability of MSC secretome to stimulate neuron survival under conditions of glutamate-induced neurotoxicity. However, the lesion volume did not shrink in these rats, and this also correlated with prominent microglia activation. We hypothesize that this could be caused by the species-specificity of the used MSC secretome and provide evidence to confirm this. Thus, we have found that allogenic rat MSC secretome was more effective than xenogenic human MSC secretome in the rat intracerebral hemorrhage model: it reduced the volume of the lesion and promoted excellent survival and neurological outcome of the treated rats. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

24 pages, 3416 KiB

Open AccessArticle

Interaction between Macrophages and Human Mesenchymal Stromal Cells Derived from Bone Marrow and Wharton’s Jelly—A Comparative Study

by Marta Dymowska, Aleksandra Aksamit, Katarzyna Zielniok, Monika Kniotek, Beata Kaleta, Aleksander Roszczyk, Michal Zych, Filip Dabrowski, Leszek Paczek and Anna Burdzinska

Pharmaceutics 2021, 13(11), 1822; https://doi.org/10.3390/pharmaceutics13111822 - 01 Nov 2021

Cited by 10 | Viewed by 2207

Abstract

Despite intensive clinical research on the use of mesenchymal stromal cells (MSCs), further basic research in this field is still required. Herein, we compared human bone marrow MSCs (BM-MSCs, n = 6) and Wharton’s jelly MSCs (WJ-MSCs, n = 6) in their ability [...] Read more.

Despite intensive clinical research on the use of mesenchymal stromal cells (MSCs), further basic research in this field is still required. Herein, we compared human bone marrow MSCs (BM-MSCs, n = 6) and Wharton’s jelly MSCs (WJ-MSCs, n = 6) in their ability to interact with human primary macrophages. Evaluation of secretory potential revealed that under pro-inflammatory stimulation, WJ-MSCs secreted significantly more IL-6 than BM-MSCs (2-fold). This difference did not translate into the effect of MSCs on macrophages: both types of MSCs significantly directed M1-like macrophages toward the M2 phenotype (based on CD206 expression) to a similar extent. This observation was consistent both in flow cytometry analysis and immunocytochemical assessment. The effect of MSCs on macrophages was sustained when IL-6 signaling was blocked with Tocilizumab. Macrophages, regardless of polarization status, enhanced chemotaxis of both BM-MSCs and WJ-MSCs (p < 0.01; trans-well assay), with WJ-MSCs being significantly more responsive to M1-derived chemotactic signals than BM-MSCs. Furthermore, WJ-MSCs increased their motility (scratch assay) when exposed to macrophage-conditioned medium while BM-MSCs did not. These results indicate that although both BM-MSCs and WJ-MSCs have the ability to reciprocally interact with macrophages, the source of MSCs could slightly but significantly modify the response under clinical settings. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

26 pages, 3313 KiB

Open AccessArticle

In Vitro Cellular and Molecular Interplay between Human Foreskin-Derived Mesenchymal Stromal/Stem Cells and the Th17 Cell Pathway

by Mehdi Najar, Makram Merimi, Wissam H. Faour, Catherine A. Lombard, Douâa Moussa Agha, Yassine Ouhaddi, Etienne M. Sokal, Laurence Lagneaux and Hassan Fahmi

Pharmaceutics 2021, 13(10), 1736; https://doi.org/10.3390/pharmaceutics13101736 - 19 Oct 2021

Cited by 7 | Viewed by 2636

Abstract

Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed [...] Read more.

Foreskin, considered a biological waste material, has been shown to be a reservoir of therapeutic cells. The immunomodulatory properties of mesenchymal stromal/stem cells (MSCs) from the foreskin (FSK-MSCs) are being evaluated in cell-based therapy for degenerative, inflammatory and autoimmune disorders. Within the injured/inflamed tissue, proinflammatory lymphocytes such as IL-17-producing T helper cells (Th17) may interact with the stromal microenvironment, including MSCs. In this context, MSCs may encounter different levels of T cells as well as specific inflammatory signals. Uncovering the cellular and molecular changes during this interplay is central for developing an efficient and safe immunotherapeutic tool. To this end, an in vitro human model of cocultures of FSK-MSCs and T cells was established. These cocultures were performed at different cell ratios in the presence of an inflammatory setting. After confirming that FSK-MSCs respond to ISCT criteria by showing a typical phenotype and multilineage potential, we evaluated by flow cytometry the expression of Th17 cell markers IL-17A, IL23 receptor and RORγt within the lymphocyte population. We also measured 15 human Th17 pathway-related cytokines. Regardless of the T cell/MSC ratio, we observed a significant increase in IL-17A expression associated with an increase in IL-23 receptor expression. Furthermore, we observed substantial modulation of IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40, and TNF-α secretion. These findings suggest that FSK-MSCs are receptive to their environment and modulate the T cell response accordingly. The changes within the secretome of the stromal and immune environment are likely relevant for the therapeutic effect of MSCs. FSK-MSCs represent a valuable cellular product for immunotherapeutic purposes that needs to be further clarified and developed. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

15 pages, 4968 KiB

Open AccessArticle

Tailored Hydrogels as Delivery Platforms for Conditioned Medium from Mesenchymal Stem Cells in a Model of Acute Colitis in Mice

by Juan Sendon-Lago, Lorena Garcia-del Rio, Noemi Eiro, Patricia Diaz-Rodriguez, Leandro Avila, Luis O. Gonzalez, Francisco J. Vizoso, Roman Perez-Fernandez and Mariana Landin

Pharmaceutics 2021, 13(8), 1127; https://doi.org/10.3390/pharmaceutics13081127 - 23 Jul 2021

Cited by 12 | Viewed by 2711

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly prevalent and current therapies are not completely effective. Mesenchymal stem cells are emerging as a promising therapeutic option. Here, the effect of local hydrogel application loaded with conditioned medium [...] Read more.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is increasingly prevalent and current therapies are not completely effective. Mesenchymal stem cells are emerging as a promising therapeutic option. Here, the effect of local hydrogel application loaded with conditioned medium (CM) from human uterine cervical stem cells (hUCESC-CM) in an experimental acute colitis mice model has been evaluated. Colitis induction was carried out in C57BL/6 mice by dissolving dextran sulfate sodium (DSS) in drinking water for nine days. Ulcers were treated by rectal administration of either mesalazine (as positive control) or a mucoadhesive and thermosensitive hydrogel loaded with hUCESC-CM (H-hUCESC-CM). Body weight changes, colon length, and histopathological analysis were evaluated. In addition, pro-inflammatory TNF-α, IL-6, and IFN-γ mRNA levels were measured by qPCR. Treatment with H-hUCESC-CM inhibited body weight loss and colon shortening and induced a significant decrease in colon mucosa degeneration, as well as TNF-α, IFN-γ, and IL-6 mRNA levels. Results indicate that H-hUCESC-CM effectively alleviated DSS-induced colitis in mice, suggesting that H-hUCESC-CM may represent an attractive cell-free therapy for local treatment of IBD. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

Review

Jump to: Research

25 pages, 1798 KiB

Open AccessReview

Mesenchymal Stem/Stromal Cells and Their Paracrine Activity—Immunomodulation Mechanisms and How to Influence the Therapeutic Potential

by Rui Alvites, Mariana Branquinho, Ana C. Sousa, Bruna Lopes, Patrícia Sousa and Ana Colette Maurício

Pharmaceutics 2022, 14(2), 381; https://doi.org/10.3390/pharmaceutics14020381 - 09 Feb 2022

Cited by 41 | Viewed by 3098

Abstract

With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors [...] Read more.

With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

29 pages, 1770 KiB

Open AccessReview

Mesenchymal Stromal Cell Secretome for the Treatment of Immune-Mediated Inflammatory Diseases: Latest Trends in Isolation, Content Optimization and Delivery Avenues

by Elena Munoz-Perez, Ainhoa Gonzalez-Pujana, Manoli Igartua, Edorta Santos-Vizcaino and Rosa Maria Hernandez

Pharmaceutics 2021, 13(11), 1802; https://doi.org/10.3390/pharmaceutics13111802 - 27 Oct 2021

Cited by 30 | Viewed by 3432

Abstract

Considering the high prevalence and the complex pharmacological management of immune-mediated inflammatory diseases (IMIDs), the search for new therapeutic approaches for their treatment is vital. Although the immunomodulatory and anti-inflammatory effects of mesenchymal stromal cells (MSCs) have been extensively studied as a potential [...] Read more.

Considering the high prevalence and the complex pharmacological management of immune-mediated inflammatory diseases (IMIDs), the search for new therapeutic approaches for their treatment is vital. Although the immunomodulatory and anti-inflammatory effects of mesenchymal stromal cells (MSCs) have been extensively studied as a potential therapy in this field, direct MSC implantation presents some limitations that could slow down the clinical translation. Since the beneficial effects of MSCs have been mainly attributed to their ability to secrete a plethora of bioactive factors, their secretome has been proposed as a new and promising pathway for the treatment of IMIDs. Formed from soluble factors and extracellular vesicles (EVs), the MSC-derived secretome has been proven to elicit immunomodulatory effects that control the inflammatory processes that occur in IMIDs. This article aims to review the available knowledge on the MSC secretome, evaluating the advances in this field in terms of its composition, production and application, as well as analyzing the pending challenges in the field. Moreover, the latest research involving secretome administration in IMIDs is discussed to provide an updated state-of-the-art for this field. Finally, novel secretome delivery alternatives are reviewed, paying special attention to hydrogel encapsulation as one of the most convenient and promising strategies. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Graphical abstract

15 pages, 947 KiB

Open AccessReview

Mesenchymal Stromal Cells: Potential Option for COVID-19 Treatment

by Dragan Primorac, Martin Čemerin, Vid Matišić, Vilim Molnar, Marko Strbad, Lenart Girandon, Lucija Zenić, Miomir Knežević, Stephen Minger and Denis Polančec

Pharmaceutics 2021, 13(9), 1481; https://doi.org/10.3390/pharmaceutics13091481 - 16 Sep 2021

Cited by 3 | Viewed by 3347

Abstract

The COVID-19 pandemic has significantly impacted the way of life worldwide and continues to bring high mortality rates to at-risk groups. Patients who develop severe COVID-19 pneumonia, often complicated with ARDS, are left with limited treatment options with no targeted therapy currently available. [...] Read more.

The COVID-19 pandemic has significantly impacted the way of life worldwide and continues to bring high mortality rates to at-risk groups. Patients who develop severe COVID-19 pneumonia, often complicated with ARDS, are left with limited treatment options with no targeted therapy currently available. One of the features of COVID-19 is an overaggressive immune reaction that leads to multiorgan failure. Mesenchymal stromal cell (MSC) treatment has been in development for various clinical indications for over a decade, with a safe side effect profile and promising results in preclinical and clinical trials. Therefore, the use of MSCs in COVID-19-induced respiratory failure and ARDS was a logical step in order to find a potential treatment option for the most severe patients. In this review, the main characteristics of MSCs, their proposed mechanism of action in COVID-19 treatment and the effect of this therapy in published case reports and clinical trials are discussed. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

16 pages, 1338 KiB

Open AccessReview

Wharton’s Jelly Mesenchymal Stromal Cells and Derived Extracellular Vesicles as Post-Myocardial Infarction Therapeutic Toolkit: An Experienced View

by Noelia Muñoz-Domínguez, Santiago Roura, Cristina Prat-Vidal and Joaquim Vives

Pharmaceutics 2021, 13(9), 1336; https://doi.org/10.3390/pharmaceutics13091336 - 26 Aug 2021

Cited by 2 | Viewed by 2796

Abstract

Outstanding progress has been achieved in developing therapeutic options for reasonably alleviating symptoms and prolonging the lifespan of patients suffering from myocardial infarction (MI). Current treatments, however, only partially address the functional recovery of post-infarcted myocardium, which is in fact the major goal [...] Read more.

Outstanding progress has been achieved in developing therapeutic options for reasonably alleviating symptoms and prolonging the lifespan of patients suffering from myocardial infarction (MI). Current treatments, however, only partially address the functional recovery of post-infarcted myocardium, which is in fact the major goal for effective primary care. In this context, we largely investigated novel cell and TE tissue engineering therapeutic approaches for cardiac repair, particularly using multipotent mesenchymal stromal cells (MSC) and natural extracellular matrices, from pre-clinical studies to clinical application. A further step in this field is offered by MSC-derived extracellular vesicles (EV), which are naturally released nanosized lipid bilayer-delimited particles with a key role in cell-to-cell communication. Herein, in this review, we further describe and discuss the rationale, outcomes and challenges of our evidence-based therapy approaches using Wharton’s jelly MSC and derived EV in post-MI management. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

17 pages, 971 KiB

Open AccessFeature PaperReview

Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases

by Takeo Mukai, Kenshi Sei and Tokiko Nagamura-Inoue

Pharmaceutics 2021, 13(8), 1159; https://doi.org/10.3390/pharmaceutics13081159 - 27 Jul 2021

Cited by 9 | Viewed by 2737

Abstract

Several studies have shown that mesenchymal stromal/stem cells (MSCs) exert their neuroprotective and neurorestorative efficacy via the secretion of neurotrophic factors. Based on these studies, many clinical trials using MSCs for the treatment of neurological disorders have been conducted, and results regarding their [...] Read more.

Several studies have shown that mesenchymal stromal/stem cells (MSCs) exert their neuroprotective and neurorestorative efficacy via the secretion of neurotrophic factors. Based on these studies, many clinical trials using MSCs for the treatment of neurological disorders have been conducted, and results regarding their feasibility and efficacy have been reported. The present review aims to highlight the characteristics and basic research regarding the role of MSCs in neurological disease and to discuss the recent progress in clinical trials using MSCs to treat various neurological disorders. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Mesenchymal Stromal Cell-Derived Secretome for Immunomodulation and Tissue Remodeling

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (11 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI