Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment

Special Issue Editors
Special Issue Information
Keywords
Related Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 15334

Share This Special Issue

Special Issue Editor

Dr. Mirjana Jerkic

E-Mail Website
Guest Editor

The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1T8, Canada
Interests: stem cells (and MSCs, in particular); mitochondria; macrophages; brain and lung injury; sepsis; ischemia-reperfusion; TGFβ pathways; translational research and clinical studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to announce this thematic Special Issue on “Mesenchymal Stromal Cells (MSCs) Involvement in Human Diseases and Their Treatment”. MSCs are multipotent cells that have demonstrated promise in various preclinical disease models, including lung injury, sepsis, pneumonia, and cardiovascular diseases. MSCs are also being tested in clinical trials in critically ill patients with sepsis, in prevention of graft vs. host disease, acute lung injury, COVID-19 pneumonia, liver cirrhosis, cancer, wound healing problems, etc. Despite extensive research in the MSC field, however, our understanding of the mechanisms of their action is incomplete, and this Special Issue will advance our knowledge in this important research field.

The main scope of the issue is to highlight the current state of knowledge of molecular mechanisms by which MSCs act in health and disease, exhibit potent paracrine properties, modulate host immune responses and inflammation, interact with the environment, and orchestrate tissue repair, at both the local and systemic levels.

We welcome original research and up-to-date review papers. Generally, pure clinical research or model studies, survey studies, and correlation research are out of the scope of IJMS. However, clinical or model submissions with biomolecular experiments are welcomed.

This Special Issue is assisted by our Topical Advisory Panel Member Dr. Razieh Rabani (University of Toronto).

Dr. Mirjana Jerkić
Guest Editor

Manuscript Submission Information

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

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

MSC homing
macrophages
lung injury
inflammation
sepsis
COVID-19
heart
liver
cell therapy

Related Special Issue

Mesenchymal Stromal and Immune Cells’ Involvement in Human Diseases and Their Treatment in International Journal of Molecular Sciences (1 article)

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Editorial

Jump to: Research, Review

4 pages, 183 KiB

Open AccessEditorial

Special Issue “Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment”

by Mirjana Jerkic and Razieh Rabani

Int. J. Mol. Sci. 2024, 25(2), 1269; https://doi.org/10.3390/ijms25021269 - 20 Jan 2024

Viewed by 688

Abstract

Mesenchymal stromal cells (MSCs) are multipotent, non-hematopoietic cells that have the ability to differentiate into several mature cell types, including adipocytes, chondrocytes, osteoblasts, and myoblasts [...] Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

Research

Jump to: Editorial, Review

12 pages, 4788 KiB

Open AccessArticle

Overexpression of Alpha-1 Antitrypsin Increases the Proliferation of Mesenchymal Stem Cells by Upregulation of Cyclin D1

by Bryan Wolf, Prasanth Muralidharan, Michael Y. Lee, Wei Hua, Erica Green, Hongjun Wang and Charlie Strange

Int. J. Mol. Sci. 2024, 25(4), 2015; https://doi.org/10.3390/ijms25042015 - 7 Feb 2024

Viewed by 596

Abstract

Alpha-1 antitrypsin-overexpressing mesenchymal stromal/stem cells (AAT-MSCs) showed improved innate properties with a faster proliferation rate when studied for their protective effects in mouse models of diseases. Here, we investigated the potential mechanism(s) by which AAT gene insertion increases MSC proliferation. Human bone marrow-derived primary or immortalized MSCs (iMSCs) or AAT-MSCs (iAAT-MSCs) were used in the study. Cell proliferation was measured by cell counting and cell cycle analysis. Possible pathways involved in the pro-proliferation effect of AAT were investigated by measuring mRNA and protein expression of key cell cycle genes. Interval cell counting showed increased proliferation in AAT-MSCs or iAAT-MSCs compared to their corresponding MSC controls. Cell cycle analysis revealed more cells progressing into the S and G2/M phases in iAAT-MSCs, with a notable increase in the cell cycle protein, Cyclin D1. Moreover, treatment with Cyclin D1 inhibitors showed that the increase in proliferation is due to Cyclin D1 and that the AAT protein is upstream and a positive regulator of Cyclin D1. Furthermore, AAT’s effect on Cyclin D1 is independent of the Wnt signaling pathway as there were no differences in the expression of regulatory proteins, including GSK3β and β-Catenin in iMSC and iAAT-MSCs. In summary, our results indicate that AAT gene insertion in an immortalized MSC cell line increases cell proliferation and growth by increasing Cyclin D1 expression and consequently causing cells to progress through the cell cycle at a significantly faster rate. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

16 pages, 2755 KiB

Open AccessArticle

Human Bone Marrow Mesenchymal Stem Cells Promote the M2 Phenotype in Macrophages Derived from STEMI Patients

by Víctor Adrián Cortés-Morales, Wendy Guadalupe Vázquez-González, Juan José Montesinos, Luis Moreno-Ruíz, Selene Salgado-Pastor, Pamela Michelle Salinas-Arreola, Karla Díaz-Duarte, Adriana Karina Chávez-Rueda and Luis Chávez-Sánchez

Int. J. Mol. Sci. 2023, 24(22), 16257; https://doi.org/10.3390/ijms242216257 - 13 Nov 2023

Cited by 1 | Viewed by 860

Abstract

Acute ST-elevation myocardial infarction (STEMI) leads to myocardial injury or necrosis, and M1 macrophages play an important role in the inflammatory response. Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are capable of modulating macrophage plasticity, principally due to their immunoregulatory capacity. In the present study, we analyzed the capacity of MSCs to modulate macrophages derived from monocytes from patients with STEMI. We analyzed the circulating levels of cytokines associated with M1 and M2 macrophages in patients with STEMI, and the levels of cytokines associated with M1 macrophages were significantly higher in patients with STEMI than in controls. BM-MSCs facilitate the generation of M1 and M2 macrophages. M1 macrophages cocultured with MSCs did not have decreased M1 marker expression, but these macrophages had an increased expression of markers of the M2 macrophage phenotype (CD14, CD163 and CD206) and IL-10 and IL-1Ra signaling-induced regulatory T cells (Tregs). M2 macrophages from patients with STEMI had an increased expression of M2 phenotypic markers in coculture with BM-MSCs, as well as an increased secretion of anti-inflammatory cytokines and an increased generation of Tregs. The findings in this study indicate that BM-MSCs have the ability to modulate the M1 macrophage response, which could improve cardiac tissue damage in patients with STEMI. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

18 pages, 3001 KiB

Open AccessArticle

Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus

by Felipe Bruno Dias de Oliveira, Eliane Antonioli, Olívia Furiama Metropolo Dias, Jean Gabriel de Souza, Sudha Agarwal, Ana Marisa Chudzinski-Tavassi and Mario Ferretti

Int. J. Mol. Sci. 2023, 24(21), 15543; https://doi.org/10.3390/ijms242115543 - 24 Oct 2023

Cited by 1 | Viewed by 1064

Abstract

Transplanted mesenchymal stromal cells (MSCs) exhibit a robust anti-inflammatory and homing capacity in response to high inflammatory signals, as observed in studies focused on rheumatic diseases that target articular cartilage (AC) health. However, AC degradation in osteoarthritis (OA) does not necessarily coincide with a highly inflammatory joint profile. Often, by the time patients seek medical attention, they already have damaged AC. In this study, we examined the therapeutic potential of a single bone marrow MSC transplant (2 × 10⁶ cells/kg_bw) through two different routes: intra-articular (MSCs-IAt) and intravenous (MSCs-IVt) in a preclinical model of low-grade inflammatory OA with an established AC degeneration. OA was induced through the destabilization of the medial meniscus (DMM) in female Wistar Kyoto rats. The animals received MSCs 9 weeks after surgery and were euthanized 4 and 12 weeks post-transplant. In vivo and ex vivo tracking of MSCs were analyzed via bioluminescence and imaging flow cytometry, respectively. Cytokine/chemokine modulation in serum and synovial fluid was measured using a multiplex panel. AC degeneration was quantified through histology, and hindlimb muscle balance was assessed with precision weighing. To our knowledge, we are the first group to show the in vivo (8 h) and ex vivo (12 h) homing of cells to the DMM–OA joint following MSCs-IVt. In the case of MSCs-IAt, the detection of cellular bioluminescence at the knee joint persisted for up to 1 week. Intriguingly, intra-articular saline injection (placebo-IAt) resulted in a worse prognosis of OA when compared to a non-invasive control (placebo-IVt) without joint injection. The systemic cytokines/chemokines profile exhibited a time-dependent variation between transplant routes, displaying a transient anti-inflammatory systemic response for both MSCs-IVt and MSCs-IAt. A single injection of MSCs, whether administered via the intra-articular or intravenous route, performed 9 weeks after DMM surgery, did not effectively inhibit AC degeneration when compared to a non-invasive control. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

16 pages, 5426 KiB

Open AccessArticle

Extracellular Vesicles from Different Sources of Mesenchymal Stromal Cells Have Distinct Effects on Lung and Distal Organs in Experimental Sepsis

by Natália G. Blanco, Natália M. Machado, Ligia L. Castro, Mariana A. Antunes, Christina M. Takiya, Monique R. O. Trugilho, Luana R. Silva, Adriana F. Paes Leme, Romênia R. Domingues, Bianca A. Pauletti, Beatriz T. Miranda, Johnatas D. Silva, Claudia C. dos Santos, Pedro L. Silva, Patricia R. M. Rocco and Fernanda F. Cruz

Int. J. Mol. Sci. 2023, 24(9), 8234; https://doi.org/10.3390/ijms24098234 - 4 May 2023

Cited by 3 | Viewed by 1791

Abstract

The effects of the administration of mesenchymal stromal cells (MSC) may vary according to the source. We hypothesized that MSC-derived extracellular vesicles (EVs) obtained from bone marrow (BM), adipose (AD), or lung (L) tissues may also lead to different effects in sepsis. We profiled the proteome from EVs as a first step toward understanding their mechanisms of action. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (SEPSIS) and SHAM (control) animals only underwent laparotomy. Twenty-four hours after surgery, animals in the SEPSIS group were randomized to receive saline or 3 × 10⁶ MSC-derived EVs from BM, AD, or L. The diffuse alveolar damage was decreased with EVs from all three sources. In kidneys, BM-, AD-, and L-EVs reduced edema and expression of interleukin-18. Kidney injury molecule-1 expression decreased only in BM- and L-EVs groups. In the liver, only BM-EVs reduced congestion and cell infiltration. The size and number of EVs from different sources were not different, but the proteome of the EVs differed. BM-EVs were enriched for anti-inflammatory proteins compared with AD-EVs and L-EVs. In conclusion, BM-EVs were associated with less organ damage compared with the other sources of EVs, which may be related to differences detected in their proteome. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

14 pages, 1872 KiB

Open AccessArticle

Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents

by Declan Byrnes, Claire H. Masterson, Hector E. Gonzales, Sean D. McCarthy, Daniel P. O’Toole and John G. Laffey

Int. J. Mol. Sci. 2023, 24(9), 8055; https://doi.org/10.3390/ijms24098055 - 29 Apr 2023

Cited by 1 | Viewed by 1573

Abstract

Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naïve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous naïve or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of naïve MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to naïve MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4⁺/CD8⁺ ratios. Systemically, granulocytes, classical monocytes, and the CD4⁺/CD8⁺ ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs—particularly preactivated MSCs—enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

19 pages, 2004 KiB

Open AccessArticle

Opposing MMP-9 Expression in Mesenchymal Stromal Cells and Head and Neck Tumor Cells after Direct 2D and 3D Co-Culture

by Anna Waltera, Daniela Schulz, Nicole Schaefer, Sabine Stoeckl, Eric Pion, Silke Haerteis, Torsten E. Reichert, Tobias Ettl and Richard J. Bauer

Int. J. Mol. Sci. 2023, 24(2), 1293; https://doi.org/10.3390/ijms24021293 - 9 Jan 2023

Cited by 4 | Viewed by 1823

Abstract

Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. In our experiments, direct 3D co-culture of BMSCs with tumor cells from the head and neck region (HNSCC) results in strong expression and secretion of MMP-9. The observed MMP-9 secretion mainly originates from BMSCs, leading to increased invasiveness. In addition to our in vitro data, we show in vivo data based on the chorioallantoic membrane (CAM) model. Our results demonstrate that MMP-9 induces hemorrhage and increased perfusion in BMSC/HNSCC co-culture. While we had previously outlined that MMP-9 expression and secretion originate from BMSCs, our data showed a strong downregulation of MMP-9 promoter activity in HNSCC cells upon direct contact with BMSCs using the luciferase activity assay. Interestingly, the 2D and 3D models of direct co-culture suggest different drivers for the downregulation of MMP-9 promoter activity. Whereas the 3D model depicts a BMSC-dependent downregulation, the 2D model shows cell density-dependent downregulation. In summary, our data suggest that the direct interaction of HNSCC cells and BMSCs promotes tumor progression by significantly facilitating angiogenesis via MMP-9 expression. On the other hand, data from 3D and 2D co-culture models indicate opposing regulation of the MMP-9 promoter in tumor cells once stromal cells are involved. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

Review

Jump to: Editorial, Research

34 pages, 1652 KiB

Open AccessReview

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

by Avinash Naraiah Mukkala, Mirjana Jerkic, Zahra Khan, Katalin Szaszi, Andras Kapus and Ori Rotstein

Int. J. Mol. Sci. 2023, 24(21), 15788; https://doi.org/10.3390/ijms242115788 - 31 Oct 2023

Cited by 3 | Viewed by 1685

Abstract

Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

19 pages, 3464 KiB

Open AccessReview

Mesenchymal Stem/Stromal Cell-Based Therapies in Systemic Rheumatic Disease: From Challenges to New Approaches for Overcoming Restrictions

by Bong-Woo Lee and Seung-Ki Kwok

Int. J. Mol. Sci. 2023, 24(12), 10161; https://doi.org/10.3390/ijms241210161 - 15 Jun 2023

Cited by 2 | Viewed by 1940

Abstract

Systemic rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, are chronic autoimmune diseases affecting multiple organs and tissues. Despite recent advances in treatment, patients still experience significant morbidity and disability. Mesenchymal stem/stromal cell (MSC)-based therapy is promising for treating systemic rheumatic diseases due to the regenerative and immunomodulatory properties of MSCs. However, several challenges need to be overcome to use MSCs in clinical practice effectively. These challenges include MSC sourcing, characterization, standardization, safety, and efficacy issues. In this review, we provide an overview of the current state of MSC-based therapies in systemic rheumatic diseases, highlighting the challenges and limitations associated with their use. We also discuss emerging strategies and novel approaches that can help overcome the limitations. Finally, we provide insights into the future directions of MSC-based therapies for systemic rheumatic diseases and their potential clinical applications. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Figure 1

20 pages, 1497 KiB

Open AccessReview

Mesenchymal Stem Cells in Acquired Aplastic Anemia: The Spectrum from Basic to Clinical Utility

by Xing-An Wang, Ju-Pi Li, Kang-Hsi Wu, Shun-Fa Yang and Yu-Hua Chao

Int. J. Mol. Sci. 2023, 24(5), 4464; https://doi.org/10.3390/ijms24054464 - 24 Feb 2023

Cited by 4 | Viewed by 2047

Abstract

Aplastic anemia (AA), a rare but potentially life-threatening disease, is a paradigm of bone marrow failure syndromes characterized by pancytopenia in the peripheral blood and hypocellularity in the bone marrow. The pathophysiology of acquired idiopathic AA is quite complex. Mesenchymal stem cells (MSCs), an important component of the bone marrow, are crucial in providing the specialized microenvironment for hematopoiesis. MSC dysfunction may result in an insufficient bone marrow and may be associated with the development of AA. In this comprehensive review, we summarized the current understanding about the involvement of MSCs in the pathogenesis of acquired idiopathic AA, along with the clinical application of MSCs for patients with the disease. The pathophysiology of AA, the major properties of MSCs, and results of MSC therapy in preclinical animal models of AA are also described. Several important issues regarding the clinical use of MSCs are discussed finally. With evolving knowledge from basic studies and clinical applications, we anticipate that more patients with the disease can benefit from the therapeutic effects of MSCs in the near future. Full article

(This article belongs to the Special Issue Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment)

► Show Figures

Journal Menu

Journal Browser

Mesenchymal Stromal Cells’ Involvement in Human Diseases and Their Treatment

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (10 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI