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The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 52683

Special Issue Editor

Prof. Dr. Monia Orciani

E-Mail Website
Guest Editor
Department of Clinical and Molecular Sciences—Histology, Università Politecnica delle Marche, 60126 Ancona, Italy
Interests: mesenchymal stem cells; inflammation; paracrine effects; skin pathologies; miRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammatory diseases include a vast array of disorders characterized by inflammation, ranging from asthma and autoimmune pathologies up to fibrotic diseases. Fibrosis is in fact defined as a pathological feature of most chronic inflammatory diseases. Among fibrotic diseases, pulmonary fibrosis deserves particular attention. In recent decades, scientific has research tried to address the question of the role of mesenchymal stem cells (MSCs) on inflammatory and fibrotic diseases; MSCs are able to modulate the inflamed microenvironment by secreting pro- and/or anti-inflammatory cytokines. The link between MSCs and inflammation is actually still debated: In different models, it has been observed that MSCs can sustain or counteract inflammation.

New insights about MSCs/inflammation/fibrotic diseases are requested to improve the knowledge of the mechanisms regulating these pathologies and to focus on the potential therapeutic role of MSCs.

Dr. Monia Orciani
Guest Editor

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • MSCs
  • Inflammation
  • Fibrosis
  • Lung
  • Cytokines
  • Paracrine effect

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Published Papers (15 papers)

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Editorial

Jump to: Research, Review

3 pages, 191 KiB  
Editorial
Special Issue “The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases”
by Mariangela Di Vincenzo and Monia Orciani
Int. J. Mol. Sci. 2023, 24(10), 8578; https://doi.org/10.3390/ijms24108578 - 11 May 2023
Viewed by 857
Abstract
This Special Issue focused on the complex role played by MSCs in the onset and development of inflammatory diseases: MSCs can support or counteract inflammation and, in turn, the onset of disease [...] Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)

Research

Jump to: Editorial, Review

15 pages, 4365 KiB  
Article
The Secretome of Preconditioned Mesenchymal Stem Cells Drives Polarization and Reprogramming of M2a Macrophages toward an IL-10-Producing Phenotype
by Michelle Holthaus, Nivethiha Santhakumar, Thorsten Wahlers and Adnana Paunel-Görgülü
Int. J. Mol. Sci. 2022, 23(8), 4104; https://doi.org/10.3390/ijms23084104 - 7 Apr 2022
Cited by 16 | Viewed by 2438
Abstract
The preconditioning of mesenchymal stem cells (MSCs) has been recognized as an attractive tool to improve their regenerative and immunomodulatory capacities based on their paracrine effects. In this study, we examined the potential of an MSC-conditioned medium (MSC-CM) to alter the phenotype of [...] Read more.
The preconditioning of mesenchymal stem cells (MSCs) has been recognized as an attractive tool to improve their regenerative and immunomodulatory capacities based on their paracrine effects. In this study, we examined the potential of an MSC-conditioned medium (MSC-CM) to alter the phenotype of murine macrophages and to drive reprogramming toward an anti-inflammatory, M2-like state in vitro. We further explored the impact of MSC cytokine preconditioning on the immunosuppressive properties of the MSC secretome. The MSC-CM suppressed the expression of proinflammatory genes in murine M1 macrophages, but only the CM from preconditioned MSCs (preMSC-CM) downregulated their expression during M1 polarization. Remarkably, only the preMSC-CM significantly increased the expression of M2a-, M2b- and M2c-specific genes and proteins during M2a polarization. Further, macrophages were found to secrete high levels of anti-inflammatory IL-10. Similarly, M2a macrophages cultured in the presence of the preMSC-CM displayed an enhanced expression of M2b/M2c-specific markers, suggesting that the secretome of preMSC promotes the repolarization of M2a-like macrophages to M2b/M2c subtypes. The preMSC-CM was found to be enriched in molecules involved in M2 polarization. Additionally, a unique downregulation of extracellular matrix components was observed. Altogether, the preMSC-CM may provide an attractive strategy to dampen inflammation by suppressing the expression of proinflammatory mediators and promoting the polarization and phenotype switch of M2a cells to IL-10-secreting M2b/M2c-like macrophages. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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10 pages, 1826 KiB  
Article
Protective Effect of Membrane-Free Stem Cells against Lipopolysaccharide and Interferon-Gamma-Stimulated Inflammatory Responses in RAW 264.7 Macrophages
by Mei Tong He, Hye Sook Park, Young Sil Kim, Ah Young Lee and Eun Ju Cho
Int. J. Mol. Sci. 2021, 22(13), 6894; https://doi.org/10.3390/ijms22136894 - 27 Jun 2021
Cited by 11 | Viewed by 2552
Abstract
Recently, adipose-derived stem cells (ADSCs) are considered to be ideal for application in cell therapy or tissue regeneration, mainly due to their wide availability and easy access. In this study, we examined the anti-inflammatory effects of membrane-free stem cell extract (MFSC-Ex) derived from [...] Read more.
Recently, adipose-derived stem cells (ADSCs) are considered to be ideal for application in cell therapy or tissue regeneration, mainly due to their wide availability and easy access. In this study, we examined the anti-inflammatory effects of membrane-free stem cell extract (MFSC-Ex) derived from ADSCs against lipopolysaccharide (LPS)/interferon-gamma (IFN-γ) on RAW 264.7 macrophage cells. Exposure of RAW macrophages to LPS and IFN-γ stimuli induced high levels of nitric oxide (NO), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) production. However, pretreatment with MFSC-Ex inhibited LPS/IFN-γ-induced these pro-inflammatory mediators. To clarify the molecular mechanisms underlying the anti-inflammatory property of MFSC-Ex, we analyzed nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) protein expressions by Western blotting. Our study showed that treatment of MFSC-Ex significantly down-regulated inducible nitric oxide synthase (iNOS) and COX-2 protein expressions. Furthermore, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was also blocked by treatment with MFSC-Ex, indicating that inhibitory effect of MFSC-Ex on MAPK signaling cascade may attribute to inactivation of NF-κB. From these findings, we suggest that MFSC-Ex exert anti-inflammatory activities, which suppressed LPS/IFN-γ-induced production of NO, COX-2 and PGE2 by regulation of NF-κB and MAPK signaling pathway in RAW 264.7 macrophages. In conclusion, MFSC-Ex might provide a new therapeutic opportunity to treatment of inflammatory-related diseases. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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12 pages, 11153 KiB  
Article
Extracellular Vesicles Are More Potent Than Adipose Mesenchymal Stromal Cells to Exert an Anti-Fibrotic Effect in an In Vitro Model of Systemic Sclerosis
by Pauline Rozier, Marie Maumus, Claire Bony, Alexandre Thibault Jacques Maria, Florence Sabatier, Christian Jorgensen, Philippe Guilpain and Danièle Noël
Int. J. Mol. Sci. 2021, 22(13), 6837; https://doi.org/10.3390/ijms22136837 - 25 Jun 2021
Cited by 9 | Viewed by 2077
Abstract
Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy [...] Read more.
Systemic sclerosis (SSc) is a complex disorder resulting from dysregulated interactions between the three main pathophysiological axes: fibrosis, immune dysfunction, and vasculopathy, with no specific treatment available to date. Adipose tissue-derived mesenchymal stromal cells (ASCs) and their extracellular vesicles (EVs) have proved efficacy in pre-clinical murine models of SSc. However, their precise action mechanism is still not fully understood. Because of the lack of availability of fibroblasts isolated from SSc patients (SSc-Fb), our aim was to determine whether a TGFβ1-induced model of human myofibroblasts (Tβ-Fb) could reproduce the characteristics of SSc-Fb and be used to evaluate the anti-fibrotic function of ASCs and their EVs. We found out that Tβ-Fb displayed the main morphological and molecular features of SSc-Fb, including the enlarged hypertrophic morphology and expression of several markers associated with the myofibroblastic phenotype. Using this model, we showed that ASCs were able to regulate the expression of most myofibroblastic markers on Tβ-Fb and SSc-Fb, but only when pre-stimulated with TGFβ1. Of interest, ASC-derived EVs were more effective than parental cells for improving the myofibroblastic phenotype. In conclusion, we provided evidence that Tβ-Fb are a relevant model to mimic the main characteristics of SSc fibroblasts and investigate the mechanism of action of ASCs. We further reported that ASC-EVs are more effective than parental cells suggesting that the TGFβ1-induced pro-fibrotic environment may alter the function of ASCs. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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14 pages, 2011 KiB  
Article
MIT-001 Restores Human Placenta-Derived Mesenchymal Stem Cells by Enhancing Mitochondrial Quiescence and Cytoskeletal Organization
by Won Dong Yu, Yu Jin Kim, Min Jeong Cho, Gi Jin Kim, Soon Ha Kim, Myung Joo Kim, Jung Jae Ko and Jae Ho Lee
Int. J. Mol. Sci. 2021, 22(10), 5062; https://doi.org/10.3390/ijms22105062 - 11 May 2021
Cited by 5 | Viewed by 3845
Abstract
Inflammation is a major cause of several chronic diseases and is reported to be recovered by the immuno-modulation of mesenchymal stem cells (MSCs). While most studies have focussed on the anti-inflammatory roles of MSCs in stem cell therapy, the impaired features of MSCs, [...] Read more.
Inflammation is a major cause of several chronic diseases and is reported to be recovered by the immuno-modulation of mesenchymal stem cells (MSCs). While most studies have focussed on the anti-inflammatory roles of MSCs in stem cell therapy, the impaired features of MSCs, such as the loss of homeostasis by systemic aging or pathologic conditions, remain incompletely understood. In this study, we investigated whether the altered phenotypes of human placenta-derived MSCs (hPD-MSCs) exposed to inflammatory cytokines, including TNF-α and IFN-γ, could be protected by MIT-001, a small anti-inflammatory and anti-necrotic molecule. MIT-001 promoted the spindle-like shape and cytoskeletal organization extending across the long cell axis, whereas hPD-MSCs exposed to TNF-α/IFN-γ exhibited increased morphological heterogeneity with an abnormal cell shape and cytoskeletal disorganization. Importantly, MIT-001 improved mitochondrial distribution across the cytoplasm. MIT-001 significantly reduced basal respiration, ATP production, and cellular ROS levels and augmented the spare respiratory capacity compared to TNF-α/IFN-γ-exposed hPD-MSCs, indicating enhanced mitochondrial quiescence and homeostasis. In conclusion, while TNF-α/IFN-γ-exposed MSCs lost homeostasis and mitochondrial quiescence by becoming over-activated in response to inflammatory cytokines, MIT-001 was able to rescue mitochondrial features and cellular phenotypes. Therefore, MIT-001 has therapeutic potential for clinical applications to treat mitochondrion-related inflammatory diseases. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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14 pages, 1924 KiB  
Article
Extracellular Vesicles Do Not Mediate the Anti-Inflammatory Actions of Mouse-Derived Adipose Tissue Mesenchymal Stem Cells Secretome
by María Carmen Carceller, María Isabel Guillén, María Luisa Gil and María José Alcaraz
Int. J. Mol. Sci. 2021, 22(3), 1375; https://doi.org/10.3390/ijms22031375 - 29 Jan 2021
Cited by 8 | Viewed by 2045
Abstract
Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects [...] Read more.
Adipose tissue represents an abundant source of mesenchymal stem cells (MSC) for therapeutic purposes. Previous studies have demonstrated the anti-inflammatory potential of adipose tissue-derived MSC (ASC). Extracellular vesicles (EV) present in the conditioned medium (CM) have been shown to mediate the cytoprotective effects of human ASC secretome. Nevertheless, the role of EV in the anti-inflammatory effects of mouse-derived ASC is not known. The current study has investigated the influence of mouse-derived ASC CM and its fractions on the response of mouse-derived peritoneal macrophages against lipopolysaccharide (LPS). CM and its soluble fraction reduced the release of pro-inflammatory cytokines, adenosine triphosphate and nitric oxide in stimulated cells. They also enhanced the migration of neutrophils or monocytes, in the absence or presence of LPS, respectively, which is likely related to the presence of chemokines, and reduced the phagocytic response. The anti-inflammatory effect of CM may be dependent on the regulation of toll-like receptor 4 expression and nuclear factor-κB activation. Our results demonstrate the anti-inflammatory effects of mouse-derived ASC secretome in mouse-derived peritoneal macrophages stimulated with LPS and show that they are not mediated by EV. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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18 pages, 3419 KiB  
Article
How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis
by Martina Bonifazi, Mariangela Di Vincenzo, Miriam Caffarini, Federico Mei, Michele Salati, Lina Zuccatosta, Majed Refai, Monica Mattioli-Belmonte, Stefano Gasparini and Monia Orciani
Int. J. Mol. Sci. 2020, 21(21), 8140; https://doi.org/10.3390/ijms21218140 - 30 Oct 2020
Cited by 12 | Viewed by 2149
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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14 pages, 3223 KiB  
Article
Anti-Fibrotic Effect of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells on Skeletal Muscle Cells, Mediated by Secretion of MMP-1
by Alee Choi, Sang Eon Park, Jang Bin Jeong, Suk-joo Choi, Soo-young Oh, Gyu Ha Ryu, Jeehun Lee, Hong Bae Jeon and Jong Wook Chang
Int. J. Mol. Sci. 2020, 21(17), 6269; https://doi.org/10.3390/ijms21176269 - 29 Aug 2020
Cited by 13 | Viewed by 3358
Abstract
Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis [...] Read more.
Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton’s jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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18 pages, 3162 KiB  
Article
Differentiation of Human Cardiac Atrial Appendage Stem Cells into Adult Cardiomyocytes: A Role for the Wnt Pathway?
by Leen Willems, Annick Daniëls, Yanick Fanton, Loes Linsen, Lize Evens, Virginie Bito, Jeroen Declercq, Jean-Luc Rummens, Karen Hensen and Marc Hendrikx
Int. J. Mol. Sci. 2020, 21(11), 3931; https://doi.org/10.3390/ijms21113931 - 30 May 2020
Cited by 7 | Viewed by 3806
Abstract
Human cardiac stem cells isolated from atrial appendages based on aldehyde dehydrogenase activity (CASCs) can be expanded in vitro and differentiate into mature cardiomyocytes. In this study, we assess whether Wnt activation stimulates human CASC proliferation, whereas Wnt inhibition induces cardiac maturation. CASCs [...] Read more.
Human cardiac stem cells isolated from atrial appendages based on aldehyde dehydrogenase activity (CASCs) can be expanded in vitro and differentiate into mature cardiomyocytes. In this study, we assess whether Wnt activation stimulates human CASC proliferation, whereas Wnt inhibition induces cardiac maturation. CASCs were cultured as described before. Conventional PCR confirmed the presence of the Frizzled receptors. Small-molecule inhibitors (IWP2, C59, XAV939, and IWR1-endo) and activator (CHIR99021) of the Wnt/β -catenin signaling pathway were applied, and the effect on β-catenin and target genes for proliferation and differentiation was assessed by Western blot and RT-qPCR. CASCs express multiple early cardiac differentiation markers and are committed toward myocardial differentiation. They express several Frizzled receptors, suggesting a role for Wnt signaling in clonogenicity, proliferation, and differentiation. Wnt activation increases total and active β-catenin levels. However, this does not affect CASC proliferation or clonogenicity. Wnt inhibition upregulated early cardiac markers but could not induce mature myocardial differentiation. When CASCs are committed toward myocardial differentiation, the Wnt pathway is active and can be modulated. However, despite its role in cardiogenesis and myocardial differentiation of pluripotent stem-cell populations, our data indicate that Wnt signaling has limited effects on CASC clonogenicity, proliferation, and differentiation. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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Review

Jump to: Editorial, Research

20 pages, 11852 KiB  
Review
State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis
by Dae Gyu Kwon, Myung Ku Kim, Yoon Sang Jeon, Yoon Cheol Nam, Jin Seong Park and Dong Jin Ryu
Int. J. Mol. Sci. 2022, 23(3), 1618; https://doi.org/10.3390/ijms23031618 - 30 Jan 2022
Cited by 30 | Viewed by 5565
Abstract
Osteoarthritis (OA) has generally been introduced as a degenerative disease; however, it has recently been understood as a low-grade chronic inflammatory process that could promote symptoms and accelerate the progression of OA. Current treatment strategies, including corticosteroid injections, have no impact on the [...] Read more.
Osteoarthritis (OA) has generally been introduced as a degenerative disease; however, it has recently been understood as a low-grade chronic inflammatory process that could promote symptoms and accelerate the progression of OA. Current treatment strategies, including corticosteroid injections, have no impact on the OA disease progression. Mesenchymal stem cells (MSCs) based therapy seem to be in the spotlight as a disease-modifying treatment because this strategy provides enlarged anti-inflammatory and chondroprotective effects. Currently, bone marrow, adipose derived, synovium-derived, and Wharton’s jelly-derived MSCs are the most widely used types of MSCs in the cartilage engineering. MSCs exert immunomodulatory, immunosuppressive, antiapoptotic, and chondrogenic effects mainly by paracrine effect. Because MSCs disappear from the tissue quickly after administration, recently, MSCs-derived exosomes received the focus for the next-generation treatment strategy for OA. MSCs-derived exosomes contain a variety of miRNAs. Exosomal miRNAs have a critical role in cartilage regeneration by immunomodulatory function such as promoting chondrocyte proliferation, matrix secretion, and subsiding inflammation. In the future, a personalized exosome can be packaged with ideal miRNA and proteins for chondrogenesis by enriching techniques. In addition, the target specific exosomes could be a gamechanger for OA. However, we should consider the off-target side effects due to multiple gene targets of miRNA. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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18 pages, 740 KiB  
Review
Mesenchymal Stem Cells Therapies on Fibrotic Heart Diseases
by Fernanda Gubert, Jaqueline Soares da Silva, Juliana F. Vasques, Renata Guedes de Jesus Gonçalves, Robertta Silva Martins, Mauro Paes Leme de Sá, Rosalia Mendez-Otero and Gisele Zapata-Sudo
Int. J. Mol. Sci. 2021, 22(14), 7447; https://doi.org/10.3390/ijms22147447 - 12 Jul 2021
Cited by 19 | Viewed by 3461
Abstract
Stem cell therapy is a promising alternative approach to heart diseases. The most prevalent source of multipotent stem cells, usually called somatic or adult stem cells (mesenchymal stromal/stem cells, MSCs) used in clinical trials is bone marrow (BM-MSCs), adipose tissue (AT-MSCs), umbilical cord [...] Read more.
Stem cell therapy is a promising alternative approach to heart diseases. The most prevalent source of multipotent stem cells, usually called somatic or adult stem cells (mesenchymal stromal/stem cells, MSCs) used in clinical trials is bone marrow (BM-MSCs), adipose tissue (AT-MSCs), umbilical cord (UC-MSCs) and placenta. Therapeutic use of MSCs in cardiovascular diseases is based on the benefits in reducing cardiac fibrosis and inflammation that compose the cardiac remodeling responsible for the maintenance of normal function, something which may end up causing progressive and irreversible dysfunction. Many factors lead to cardiac fibrosis and failure, and an effective therapy is lacking to reverse or attenuate this condition. Different approaches have been shown to be promising in surpassing the poor survival of transplanted cells in cardiac tissue to provide cardioprotection and prevent cardiac remodeling. This review includes the description of pre-clinical and clinical investigation of the therapeutic potential of MSCs in improving ventricular dysfunction consequent to diverse cardiac diseases. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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14 pages, 852 KiB  
Review
FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective
by Patrizia Pignataro, Manuela Dicarlo, Roberta Zerlotin, Chiara Zecca, Maria Teresa Dell’Abate, Cinzia Buccoliero, Giancarlo Logroscino, Silvia Colucci and Maria Grano
Int. J. Mol. Sci. 2021, 22(4), 1605; https://doi.org/10.3390/ijms22041605 - 5 Feb 2021
Cited by 53 | Viewed by 5381
Abstract
Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous [...] Read more.
Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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15 pages, 1076 KiB  
Review
The Anti-Inflammatory Properties of Mesenchymal Stem Cells in Epilepsy: Possible Treatments and Future Perspectives
by Valentina Salari, Francesca Mengoni, Federico Del Gallo, Giuseppe Bertini and Paolo Francesco Fabene
Int. J. Mol. Sci. 2020, 21(24), 9683; https://doi.org/10.3390/ijms21249683 - 18 Dec 2020
Cited by 25 | Viewed by 3773
Abstract
Mesenchymal stem cells (MSCs) are multipotent adult cells with self-renewing capacities. MSCs display specific properties, such as the ability to repair damaged tissues, resulting in optimal candidates for cell therapy against degenerative diseases. In addition to the reparative functions of MSCs, growing evidence [...] Read more.
Mesenchymal stem cells (MSCs) are multipotent adult cells with self-renewing capacities. MSCs display specific properties, such as the ability to repair damaged tissues, resulting in optimal candidates for cell therapy against degenerative diseases. In addition to the reparative functions of MSCs, growing evidence shows that these cells have potent immunomodulatory and anti-inflammatory properties. Therefore, MSCs are potential tools for treating inflammation-related neurological diseases, including epilepsy. In this regard, over the last decades, epilepsy has no longer been considered a purely neuronal pathology, since inflammatory events underlying the genesis of epilepsy have been demonstrated. This review assessed current knowledge on the use of MSCs in the treatment of epilepsy. Mostly, attention will be focused on the anti-inflammatory and immunological skills of MSCs. Understanding the mechanisms by which MSCs might modulate the severity of the disease will contribute to the development of new potential alternatives for both prophylaxis and treatment against epilepsy. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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15 pages, 751 KiB  
Review
The Crosstalk of Adipose-Derived Stem Cells (ADSC), Oxidative Stress, and Inflammation in Protective and Adaptive Responses
by Luc Rochette, Loubna Mazini, Gabriel Malka, Marianne Zeller, Yves Cottin and Catherine Vergely
Int. J. Mol. Sci. 2020, 21(23), 9262; https://doi.org/10.3390/ijms21239262 - 4 Dec 2020
Cited by 38 | Viewed by 3355
Abstract
The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells [...] Read more.
The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs is a major goal in repair medicine. Stem cells are classified by their potential to differentiate into functional cells. Compared with other sources, adipose-derived stem cells (ADSCs) have the advantage of being abundant and easy to obtain. ADSCs are considered to be tools for replacing, repairing, and regenerating dead or damaged cells. The capacity of ADSCs to maintain their properties depends on the balance of complex signals in their microenvironment. Their properties and the associated outcomes are in part regulated by reactive oxygen species, which mediate the oxidation-reduction state of cells as a secondary messenger. ADSC therapy has demonstrated beneficial effects, suggesting that secreted factors may provide protection. There is evidence that ADSCs secrete a number of cytokines, growth factors, and antioxidant factors into their microenvironment, thus regulating intracellular signaling pathways in neighboring cells. In this review, we introduce the roles of ADSCs in the protection of cells by modulating inflammation and immunity, and we develop their potential therapeutic properties. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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37 pages, 2740 KiB  
Review
State of the Art Review of Cell Therapy in the Treatment of Lung Disease, and the Potential for Aerosol Delivery
by Hosanna Brave and Ronan MacLoughlin
Int. J. Mol. Sci. 2020, 21(17), 6435; https://doi.org/10.3390/ijms21176435 - 3 Sep 2020
Cited by 26 | Viewed by 6824
Abstract
Respiratory and pulmonary diseases are among the leading causes of death globally. Despite tremendous advancements, there are no effective pharmacological therapies capable of curing diseases such as COPD (chronic obstructive pulmonary disease), ARDS (acute respiratory distress syndrome), and COVID-19. Novel and innovative therapies [...] Read more.
Respiratory and pulmonary diseases are among the leading causes of death globally. Despite tremendous advancements, there are no effective pharmacological therapies capable of curing diseases such as COPD (chronic obstructive pulmonary disease), ARDS (acute respiratory distress syndrome), and COVID-19. Novel and innovative therapies such as advanced therapy medicinal products (ATMPs) are still in early development. However, they have exhibited significant potential preclinically and clinically. There are several longitudinal studies published, primarily focusing on the use of cell therapies for respiratory diseases due to their anti-inflammatory and reparative properties, thereby hinting that they have the capability of reducing mortality and improving the quality of life for patients. The primary objective of this paper is to set out a state of the art review on the use of aerosolized MSCs and their potential to treat these incurable diseases. This review will examine selected respiratory and pulmonary diseases, present an overview of the therapeutic potential of cell therapy and finally provide insight into potential routes of administration, with a focus on aerosol-mediated ATMP delivery. Full article
(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells on Inflammatory and Fibrotic Diseases)
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