International Journal of Molecular Sciences

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17 pages, 1916 KiB

Open AccessArticle

Increased Expression of Ephrins on Immune Cells of Patients with Relapsing Remitting Multiple Sclerosis Affects Oligodendrocyte Differentiation

by Maya Golan, Avivit Krivitsky, Karin Mausner-Fainberg, Moshe Benhamou, Ifat Vigiser, Keren Regev, Hadar Kolb and Arnon Karni

Int. J. Mol. Sci. 2021, 22(4), 2182; https://doi.org/10.3390/ijms22042182 - 22 Feb 2021

Cited by 3 | Viewed by 3435

Abstract

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed [...] Read more.

The effect of the inflammatory response on regenerative processes in the brain is complex. This complexity is even greater when the cause of the tissue damage is an autoimmune response. Multiple sclerosis (MS) is an immune-mediated disease in which demyelination foci are formed in the central nervous system. The degree of repair through oligodendrocyte regeneration and remyelination is insufficient. Ephrins are membrane-bound ligands activating tyrosine kinase signaling proteins that are known to have an inhibitory effect on oligodendrocyte regeneration. In this study, we examined the expression of ephrins on immune cells of 43 patients with relapsing-remitting (RR) MS compared to 27 matched healthy controls (HC). We found an increased expression of ephrin-A2, -A3 and -B3, especially on T cell subpopulations. We also showed overexpression of ephrins on immune cells of patients with RR-MS that increases the forward signaling pathway and that expression of ephrins on immune cells has an inhibitory effect on the differentiation of oligodendrocyte precursor cells (OPCs) in vitro. Our study findings support the concept that the immune activity of T cells in patients with RR-MS has an inhibitory effect on the differentiation capacity of OPCs through the expression and forward signaling of ephrins. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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23 pages, 5057 KiB

Open AccessArticle

Impact of Digestive Inflammatory Environment and Genipin Crosslinking on Immunomodulatory Capacity of Injectable Musculoskeletal Tissue Scaffold

by Colin Shortridge, Ehsan Akbari Fakhrabadi, Leah M. Wuescher, Randall G. Worth, Matthew W. Liberatore and Eda Yildirim-Ayan

Int. J. Mol. Sci. 2021, 22(3), 1134; https://doi.org/10.3390/ijms22031134 - 24 Jan 2021

Cited by 9 | Viewed by 3035

Abstract

The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation [...] Read more.

The paracrine and autocrine processes of the host response play an integral role in the success of scaffold-based tissue regeneration. Recently, the immunomodulatory scaffolds have received huge attention for modulating inflammation around the host tissue through releasing anti-inflammatory cytokine. However, controlling the inflammation and providing a sustained release of anti-inflammatory cytokine from the scaffold in the digestive inflammatory environment are predicated upon a comprehensive understanding of three fundamental questions. (1) How does the release rate of cytokine from the scaffold change in the digestive inflammatory environment? (2) Can we prevent the premature scaffold degradation and burst release of the loaded cytokine in the digestive inflammatory environment? (3) How does the scaffold degradation prevention technique affect the immunomodulatory capacity of the scaffold? This study investigated the impacts of the digestive inflammatory environment on scaffold degradation and how pre-mature degradation can be prevented using genipin crosslinking and how genipin crosslinking affects the interleukin-4 (IL-4) release from the scaffold and differentiation of naïve macrophages (M0). Our results demonstrated that the digestive inflammatory environment (DIE) attenuates protein retention within the scaffold. Over 14 days, the encapsulated protein released 46% more in DIE than in phosphate buffer saline (PBS), which was improved through genipin crosslinking. We have identified the 0.5 (w/v) genipin concentration as an optimal concentration for improved IL-4 released from the scaffold, cell viability, mechanical strength, and scaffold porosity, and immunomodulation studies. The IL-4 released from the injectable scaffold could differentiate naïve macrophages to an anti-inflammatory (M2) lineage; however, upon genipin crosslinking, the immunomodulatory capacity of the scaffold diminished significantly, and pro-inflammatory markers were expressed dominantly. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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21 pages, 2055 KiB

Open AccessArticle

Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair

by Inés Maldonado-Lasunción, Nick O’Neill, Oliver Umland, Joost Verhaagen and Martin Oudega

Int. J. Mol. Sci. 2021, 22(2), 781; https://doi.org/10.3390/ijms22020781 - 14 Jan 2021

Cited by 10 | Viewed by 2998

Abstract

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. [...] Read more.

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. Conditioning MSC with macrophage-derived inflammation resulted in 3208 differentially expressed genes, which were annotated with significantly enriched GO terms for 1085 biological processes, 85 cellular components, and 79 molecular functions. Inflammation-mediated conditioning increased the secretion of growth factors that are key for tissue repair, including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and glial-derived neurotrophic factor. Furthermore, we found that inflammation-mediated conditioning induces transcriptomic changes that challenge the viability and mobility of MSC. Our data support the notion that macrophage-derived inflammation stimulates MSC to augment their paracrine repair-supporting activity. The results suggest that inflammatory pre-conditioning enhances the therapeutic potential of MSC transplants. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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16 pages, 2625 KiB

Open AccessArticle

Premature Activation of Immune Transcription Programs in Autoimmune-Predisposed Mouse Embryonic Stem Cells and Blastocysts

by Oktay Kirak, Eugene Ke, Kevin Y. Yang, Anna Schwarz, Lars Plate, Amy Nham, Justin R. Abadejos, Anna Valencia, R. Luke Wiseman, Kathy O. Lui and Manching Ku

Int. J. Mol. Sci. 2020, 21(16), 5743; https://doi.org/10.3390/ijms21165743 - 11 Aug 2020

Viewed by 3208

Abstract

Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, [...] Read more.

Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, we derived embryonic stem (ES) cell lines from diabetes-prone non-obese diabetic (NOD) and healthy C57BL/6 (B6) mice. While overall pluripotency markers were indistinguishable between newly derived NOD and B6 ES cells, we discovered several differentially expressed genes that normally are not expressed in ES cells. Several genes that reside in previously identified insulin-dependent diabetics (Idd) genomic regions were up-regulated in NOD ES cells. Gene set enrichment analysis showed that different groups of genes associated with immune functions are differentially expressed in NOD. Transcriptomic analysis of NOD blastocysts validated several differentially overexpressed Idd genes compared to B6. Genome-wide mapping of active histone modifications using ChIP-Seq supports active expression as the promoters and enhancers of activated genes are also marked by active histone modifications. We have also found that NOD ES cells secrete more inflammatory cytokines. Our data suggest that the known genetic predisposition of NOD to autoimmune diabetes leads to epigenetic instability of several Idd regions. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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Review

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15 pages, 638 KiB

Open AccessReview

Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction

by Yevgeniy Kim, Sanzhar Nurakhayev, Ayan Nurkesh, Zharylkasyn Zharkinbekov and Arman Saparov

Int. J. Mol. Sci. 2021, 22(5), 2715; https://doi.org/10.3390/ijms22052715 - 8 Mar 2021

Cited by 98 | Viewed by 10757

Abstract

Cardiovascular disease is the leading cause of mortality and morbidity around the globe, creating a substantial socio-economic burden as a result. Myocardial infarction is a significant contributor to the detrimental impact of cardiovascular disease. The death of cardiomyocytes following myocardial infarction causes an [...] Read more.

Cardiovascular disease is the leading cause of mortality and morbidity around the globe, creating a substantial socio-economic burden as a result. Myocardial infarction is a significant contributor to the detrimental impact of cardiovascular disease. The death of cardiomyocytes following myocardial infarction causes an immune response which leads to further destruction of tissue, and subsequently, results in the formation of non-contractile scar tissue. Macrophages have been recognized as important regulators and participants of inflammation and fibrosis following myocardial infarction. Macrophages are generally classified into two distinct groups, namely, classically activated, or M1 macrophages, and alternatively activated, or M2 macrophages. The phenotypic profile of cardiac macrophages, however, is much more diverse and should not be reduced to these two subsets. In this review, we describe the phenotypes and functions of macrophages which are present in the healthy, as well as the infarcted heart, and analyze them with respect to M1 and M2 polarization states. Furthermore, we discuss therapeutic strategies which utilize macrophage polarization towards an anti-inflammatory or reparative phenotype for the treatment of myocardial infarction. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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17 pages, 784 KiB

Open AccessReview

The Role of Mitochondria in Immune-Cell-Mediated Tissue Regeneration and Ageing

by Yu-Jih Su, Pei-Wen Wang and Shao-Wen Weng

Int. J. Mol. Sci. 2021, 22(5), 2668; https://doi.org/10.3390/ijms22052668 - 6 Mar 2021

Cited by 28 | Viewed by 7395

Abstract

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of [...] Read more.

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson’s disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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13 pages, 1093 KiB

Open AccessReview

The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

by Carl Randall Harrell, Valentin Djonov and Vladislav Volarevic

Int. J. Mol. Sci. 2021, 22(5), 2472; https://doi.org/10.3390/ijms22052472 - 1 Mar 2021

Cited by 55 | Viewed by 5451

Abstract

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and [...] Read more.

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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12 pages, 709 KiB

Open AccessReview

The Role of Macrophages in Vascular Repair and Regeneration after Ischemic Injury

by Huiling Hong and Xiao Yu Tian

Int. J. Mol. Sci. 2020, 21(17), 6328; https://doi.org/10.3390/ijms21176328 - 31 Aug 2020

Cited by 65 | Viewed by 6827

Abstract

Macrophage is one of the important players in immune response which perform many different functions during tissue injury, repair, and regeneration. Studies using animal models of cardiovascular diseases have provided a clear picture describing the effect of macrophages and their phenotype during injury [...] Read more.

Macrophage is one of the important players in immune response which perform many different functions during tissue injury, repair, and regeneration. Studies using animal models of cardiovascular diseases have provided a clear picture describing the effect of macrophages and their phenotype during injury and regeneration of various vascular beds. Many data have been generated to demonstrate that macrophages secrete many important factors including cytokines and growth factors to regulate angiogenesis and arteriogenesis, acting directly or indirectly on the vascular cells. Different subsets of macrophages may participate at different stages of vascular repair. Recent findings also suggest a direct interaction between macrophages and other cell types during the generation and repair of vasculature. In this short review, we focused our discussion on how macrophages adapt to the surrounding microenvironment and their potential interaction with other cells, in the context of vascular repair supported by evidences mostly from studies using hindlimb ischemia as a model for studying post-ischemic vascular repair. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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22 pages, 1164 KiB

Open AccessReview

Immune Cell Therapies to Improve Regeneration and Revascularization of Non-Healing Wounds

by Elena Groppa, Andrea Colliva, Roman Vuerich, Tea Kocijan and Serena Zacchigna

Int. J. Mol. Sci. 2020, 21(15), 5235; https://doi.org/10.3390/ijms21155235 - 23 Jul 2020

Cited by 8 | Viewed by 4148

Abstract

With the increased prevalence of chronic diseases, non-healing wounds place a significant burden on the health system and the quality of life of affected patients. Non-healing wounds are full-thickness skin lesions that persist for months or years. While several factors contribute to their [...] Read more.

With the increased prevalence of chronic diseases, non-healing wounds place a significant burden on the health system and the quality of life of affected patients. Non-healing wounds are full-thickness skin lesions that persist for months or years. While several factors contribute to their pathogenesis, all non-healing wounds consistently demonstrate inadequate vascularization, resulting in the poor supply of oxygen, nutrients, and growth factors at the level of the lesion. Most existing therapies rely on the use of dermal substitutes, which help the re-epithelialization of the lesion by mimicking a pro-regenerative extracellular matrix. However, in most patients, this approach is not efficient, as non-healing wounds principally affect individuals afflicted with vascular disorders, such as peripheral artery disease and/or diabetes. Over the last 25 years, innovative therapies have been proposed with the aim of fostering the regenerative potential of multiple immune cell types. This can be achieved by promoting cell mobilization into the circulation, their recruitment to the wound site, modulation of their local activity, or their direct injection into the wound. In this review, we summarize preclinical and clinical studies that have explored the potential of various populations of immune cells to promote skin regeneration in non-healing wounds and critically discuss the current limitations that prevent the adoption of these therapies in the clinics. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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27 pages, 798 KiB

Open AccessReview

The Roles of Immune Cells in the Pathogenesis of Fibrosis

by Enyu Huang, Na Peng, Fan Xiao, Dajun Hu, Xiaohui Wang and Liwei Lu

Int. J. Mol. Sci. 2020, 21(15), 5203; https://doi.org/10.3390/ijms21155203 - 22 Jul 2020

Cited by 72 | Viewed by 6991

Abstract

Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and [...] Read more.

Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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19 pages, 913 KiB

Open AccessReview

The Emerging Role of Innate Immunity in Chronic Kidney Diseases

by Philip Chiu-Tsun Tang, Ying-Ying Zhang, Max Kam-Kwan Chan, Winson Wing-Yin Lam, Jeff Yat-Fai Chung, Wei Kang, Ka-Fai To, Hui-Yao Lan and Patrick Ming-Kuen Tang

Int. J. Mol. Sci. 2020, 21(11), 4018; https://doi.org/10.3390/ijms21114018 - 4 Jun 2020

Cited by 35 | Viewed by 5379

Abstract

Renal fibrosis is a common fate of chronic kidney diseases. Emerging studies suggest that unsolved inflammation will progressively transit into tissue fibrosis that finally results in an irreversible end-stage renal disease (ESRD). Renal inflammation recruits and activates immunocytes, which largely promotes tissue scarring [...] Read more.

Renal fibrosis is a common fate of chronic kidney diseases. Emerging studies suggest that unsolved inflammation will progressively transit into tissue fibrosis that finally results in an irreversible end-stage renal disease (ESRD). Renal inflammation recruits and activates immunocytes, which largely promotes tissue scarring of the diseased kidney. Importantly, studies have suggested a crucial role of innate immunity in the pathologic basis of kidney diseases. This review provides an update of both clinical and experimental information, focused on how innate immune signaling contributes to renal fibrogenesis. A better understanding of the underlying mechanisms may uncover a novel therapeutic strategy for ESRD. Full article

(This article belongs to the Special Issue Immune Cell Mediated Tissue Regeneration)

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