International Journal of Molecular Sciences

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15 pages, 2685 KiB

Open AccessArticle

Insensitive Effects of Inflammatory Cytokines on the Reference Genes of Synovial Fluid Resident-Mesenchymal Stem Cells Derived from Rheumatoid Arthritis Patients

by Eun-Yeong Bok, Saet-Byul Kim, Gitika Thakur, Yong-Ho Choe, Seong-Ju Oh, Sun-Chul Hwang, Sun-A. Ock, Gyu-Jin Rho, Sang-Il Lee, Won-Jae Lee and Sung-Lim Lee

Int. J. Mol. Sci. 2023, 24(20), 15159; https://doi.org/10.3390/ijms242015159 - 13 Oct 2023

Cited by 1 | Viewed by 945

Abstract

Mesenchymal stem cells derived from rheumatoid arthritis patients (RA-MSCs) provide an understanding of a variety of cellular and immunological responses within the inflammatory milieu. Sustained exposure of MSCs to inflammatory cytokines is likely to exert an influence on genetic variations, including reference genes [...] Read more.

Mesenchymal stem cells derived from rheumatoid arthritis patients (RA-MSCs) provide an understanding of a variety of cellular and immunological responses within the inflammatory milieu. Sustained exposure of MSCs to inflammatory cytokines is likely to exert an influence on genetic variations, including reference genes (RGs). The sensitive effect of cytokines on the reference genes of RA-SF-MSCs may be a variation factor affecting patient-derived MSCs as well as the accuracy and reliability of data. Here, we comparatively evaluated the stability levels of nine RG candidates, namely GAPDH, ACTB, B2M, EEF1A1, TBP, RPLP0, PPIA, YWHAZ, and HPRT1, to find the most stable ones. Alteration of the RG expression was evaluated in MSCs derived from the SF of healthy donors (H-SF-MSCs) and in RA-SF-MSCs using the geNorm and NormFinder software programs. The results showed that TBP, PPIA, and YWHAZ were the most stable RGs for the normalization of H-SF-MSCs and RA-SF-MSCs using RT-qPCR, whereas ACTB, the most commonly used RG, was less stable and performed poorly. Additionally, the sensitivity of RG expression upon exposure to proinflammatory cytokines (TNF-α and IL-1β) was evaluated. RG stability was sensitive in the H-SF-MSCs exposed to TNF-α and IL-1β but insensitive in the RA-SF-MSCs. Furthermore, the normalization of IDO expression using ACTB falsely diminished the magnitude of biological significance, which was further confirmed with a functional analysis and an IDO activity assay. In conclusion, the results suggest that TBP, PPIA, and YWHAZ can be used in SF-MSCs, regardless of their exposure to inflammatory cytokines. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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20 pages, 6723 KiB

Open AccessArticle

Inflammatory Mesenchymal Stem Cells Express Abundant Membrane-Bound and Soluble Forms of C-Type Lectin-like CD248

by Melissa Payet, Franck Ah-Pine, Xavier Guillot and Philippe Gasque

Int. J. Mol. Sci. 2023, 24(11), 9546; https://doi.org/10.3390/ijms24119546 - 31 May 2023

Cited by 3 | Viewed by 1425

Abstract

CD248 (endosialin) belongs to a glycoprotein family that also includes thrombomodulin (CD141), CLEC14A, and CD93 (AA4) stem cell markers. We analyzed the regulated expression of CD248 in vitro using skin (HFFF) and synovial (FLS) mesenchymal stem cell lines, and in fluid and tissue [...] Read more.

CD248 (endosialin) belongs to a glycoprotein family that also includes thrombomodulin (CD141), CLEC14A, and CD93 (AA4) stem cell markers. We analyzed the regulated expression of CD248 in vitro using skin (HFFF) and synovial (FLS) mesenchymal stem cell lines, and in fluid and tissue samples of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Cells were incubated with either rhVEGF₁₆₅, bFGF, TGF-β1, IL1-β, TNF-α, TGFβ1, IFN-γ, or PMA (Phorbol ester). There was no statistically significant change in membrane expression. A soluble (s) form of cleaved CD248 (sCD248) was detected after cell treatment with IL1-β and PMA. Matrix metalloprotease (MMP) MMP-1 and MMP-3 mRNAs were significantly up-regulated by IL1-β and PMA. A broad MMP inhibitor blocked the release of soluble CD248. In RA synovial tissue, we identified CD90⁺ perivascular MSCs double-stained for CD248 and VEGF. High sCD248 levels were detected in synovial fluid from RA. In culture, subpopulations of CD90⁺ CD14⁻ RA MSCs were either identified as CD248⁺ or CD141⁺ cells but CD93⁻. CD248 is abundantly expressed by inflammatory MSCs and shed in an MMP-dependent manner in response to cytokines and pro-angiogenic growth factors. Both membrane-bound and soluble CD248 (acting as a decoy receptor) may contribute to RA pathogenesis. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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12 pages, 2172 KiB

Open AccessArticle

Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function?

by Hyeri Park, Jin Seok, Jun Hyeong You, Dae Hyun Lee, Ja-Yun Lim and Gi Jin Kim

Int. J. Mol. Sci. 2022, 23(24), 16009; https://doi.org/10.3390/ijms232416009 - 16 Dec 2022

Cited by 4 | Viewed by 1688

Abstract

Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of [...] Read more.

Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 10⁵) and high (5 × 10⁵) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p < 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p < 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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15 pages, 2738 KiB

Open AccessArticle

Cellular and Biochemical Characterization of Mesenchymal Stem Cells from Killian Nasal Polyp

by Maria Mesuraca, Clelia Nisticò, Nicola Lombardo, Giovanna Lucia Piazzetta, Nadia Lobello and Emanuela Chiarella

Int. J. Mol. Sci. 2022, 23(21), 13214; https://doi.org/10.3390/ijms232113214 - 30 Oct 2022

Cited by 8 | Viewed by 1537

Abstract

Killian’s (antrochoanal) polyp is a unilateral nasal polypoid lesion of the maxillary sinus especially affecting children and young adults with unilateral nasal obstruction, pus discharge, and headache. Although its etiology is unclear, chronic inflammation, autoreactivity, allergies, and viral infections are implicated in its [...] Read more.

Killian’s (antrochoanal) polyp is a unilateral nasal polypoid lesion of the maxillary sinus especially affecting children and young adults with unilateral nasal obstruction, pus discharge, and headache. Although its etiology is unclear, chronic inflammation, autoreactivity, allergies, and viral infections are implicated in its formation and development, causing nasal tissue remodeling. In this context, we isolated and cultured mesenchymal stem cells from surgical biopsies of three patients with Killian nasal polyp (KNP-MSCs) while healthy nasal tissue (HNT-MSCs) was used as control. Our results demonstrated that KNP-MSCs exhibited reduced cell proliferation compared to HNT-MSCs, and migrated less than the control, showing a partial epithelial phenotype with low mRNA levels of I-CAM and a significant increase of E-cad. Subsequently, both MSCs were induced to osteoblastic or adipocyte differentiation for up to 20 days. KNP-MSCs underwent to differentiate into osteoblasts but exhibited reduced ALP activity and calcium deposits and low mRNA levels of osteogenesis-associated genes compared to osteogenic induced-HNT-MSCs. Conversely, KNP-MSCs and HNT-MSCs have shown the same adipogenic differentiation potential, with a similar lipid droplet amount, adipocyte gene expression, and triacylglycerols content. Taken together, these results first demonstrated the cellular and molecular characterization of MSCs derived from the Killian nasal polyp. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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Review

Jump to: Research

18 pages, 832 KiB

Open AccessReview

In Search of the Holy Grail: Stem Cell Therapy as a Novel Treatment of Heart Failure with Preserved Ejection Fraction

by Olaf Domaszk, Aleksandra Skwarek and Małgorzata Wojciechowska

Int. J. Mol. Sci. 2023, 24(5), 4903; https://doi.org/10.3390/ijms24054903 - 3 Mar 2023

Cited by 1 | Viewed by 2293

Abstract

Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, [...] Read more.

Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, a growing body of evidence suggests stem cell transplantation, due to its immunomodulatory effect, may decrease fibrosis and improve microcirculation and therefore, could be the first etiology-based therapy of the disease. In this review, we explain the complex pathogenesis of HFpEF, delineate the beneficial effects of stem cells in cardiovascular therapy, and summarize the current knowledge concerning cell therapy in diastolic dysfunction. Furthermore, we identify outstanding knowledge gaps that may indicate directions for future clinical studies. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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12 pages, 1085 KiB

Open AccessReview

Therapeutic Potential of d-MAPPS™ for Ocular Inflammatory Diseases and Regeneration of Injured Corneal and Retinal Tissue

by Carl Randall Harrell

Int. J. Mol. Sci. 2022, 23(21), 13528; https://doi.org/10.3390/ijms232113528 - 4 Nov 2022

Viewed by 1359

Abstract

The invasion of microbial pathogens and/or sterile inflammation caused by physical/chemical injuries, increased ocular pressure, oxidative stress, and ischemia could lead to the generation of detrimental immune responses in the eyes, which result in excessive tissue injury and vision loss. The bioavailability of [...] Read more.

The invasion of microbial pathogens and/or sterile inflammation caused by physical/chemical injuries, increased ocular pressure, oxidative stress, and ischemia could lead to the generation of detrimental immune responses in the eyes, which result in excessive tissue injury and vision loss. The bioavailability of eye drops that are enriched with immunoregulatory and trophic factors which may concurrently suppress intraocular inflammation and promote tissue repair and regeneration is generally low. We recently developed “derived- Multiple Allogeneic Proteins Paracrine Signaling regenerative biologics platform technology d-MAPPS™”, a bioengineered biological product which is enriched with immunomodulatory and trophic factors that can efficiently suppress detrimental immune responses in the eye and promote the repair and regeneration of injured corneal and retinal tissues. The results obtained in preclinical and clinical studies showed that d-MAPPS™ increased the viability of injured corneal cells, inhibited the production of inflammatory cytokines in immune cells, alleviated inflammation, and restored vision loss in patients suffering from meibomian gland dysfunction and dry eye disease. Herewith, we emphasized molecular mechanisms responsible for the therapeutic efficacy of d-MAPPS™ and we presented the main beneficial effects of d-MAPPS™ in clinical settings, indicating that the topical administration of d-MAPPS™ could be considered a new therapeutic approach for the treatment of ocular inflammatory diseases and for the repair and regeneration of injured corneal and retinal tissues. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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15 pages, 1000 KiB

Open AccessReview

Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Ocular Graft-Versus-Host Disease

by Carl Randall Harrell, Valentin Djonov and Vladislav Volarevic

Int. J. Mol. Sci. 2022, 23(21), 13254; https://doi.org/10.3390/ijms232113254 - 31 Oct 2022

Cited by 5 | Viewed by 2299

Abstract

Ocular GVHD (oGVHD), manifested by severe injury of corneal epithelial cells, meibomian and lacrimal glands’ dysfunction, is a serious complication of systemic GVHD which develops as a consequence of donor T and natural killer cell-driven inflammation in the eyes of patients who received [...] Read more.

Ocular GVHD (oGVHD), manifested by severe injury of corneal epithelial cells, meibomian and lacrimal glands’ dysfunction, is a serious complication of systemic GVHD which develops as a consequence of donor T and natural killer cell-driven inflammation in the eyes of patients who received allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSC) are, due to their enormous differentiation potential and immunosuppressive characteristics, considered as a potentially new remedy in ophthalmology. MSC differentiate in corneal epithelial cells, suppress eye inflammation, and restore meibomian and lacrimal glands’ function in oGVHD patients. MSC-sourced exosomes (MSC-Exos) are extracellular vesicles that contain MSC-derived growth factors and immunoregulatory proteins. Due to the lipid membrane and nano-sized dimension, MSC-Exos easily by-pass all biological barriers in the eyes and deliver their cargo directly in injured corneal epithelial cells and eye-infiltrated leukocytes, modulating their viability and function. As cell-free agents, MSC-Exos address all safety issues related to the transplantation of their parental cells, including the risk of unwanted differentiation and aggravation of intraocular inflammation. In this review article, we summarized current knowledge about molecular mechanisms which are responsible for beneficial effects of MSC and MSC-Exos in the therapy of inflammatory eye diseases, emphasizing their therapeutic potential in the treatment of oGVHD. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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20 pages, 578 KiB

Open AccessReview

Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology

by Kaiting Ning, Baoqiang Yang, Meng Chen, Guigui Man, Shuaiting Liu, Dong-en Wang and Huiyun Xu

Int. J. Mol. Sci. 2022, 23(19), 11928; https://doi.org/10.3390/ijms231911928 - 7 Oct 2022

Cited by 9 | Viewed by 3058

Abstract

Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression [...] Read more.

Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression of BMSCs have indicated that BMSCs represent heterogeneous populations, and the natural characteristics of BMSCs make it difficult to identify the specific subpopulations in pathological processes which are often obscured by bulk analysis of the total BMSCs. Meanwhile, the therapeutic effect of total BMSCs is often less effective partly due to their heterogeneity. Therefore, understanding the functional heterogeneity of the BMSC subpopulations under different physiological and pathological conditions could have major ramifications for global health. Here, we summarize the recent progress of functional heterogeneity of BMSC subpopulations in physiology and pathology. Targeting tissue-resident single BMSC subpopulation offers a potentially innovative therapeutic strategy and improves BMSC effectiveness in clinical application. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells in Health and Disease 2.0)

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