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Stem Cell-Immune Function and Cardiac Regeneration

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 47336

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Special Issue Editor

Prof. Dr. Gustav Steinhoff

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Guest Editor

Director, Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
Interests: cardiac regeneration; stem cell therapy; cardiovascular disease pathomechanism

Special Issue Information

Dear Colleagues,

The development of stem-cell-based and regenerative therapies for cardiovascular and other diseases has faced an unexpected roadblock in clinical translation. Upcoming knowledge from clinical research points in the direction of bone marrow stem cell/immune progenitor cell senescence by epigenetic and somatic mutations is the potential cause. Moreover, not only is modification of tissue repair mechanisms the consequence of stem cell mutations and DNA-pathology, but these may also form the cause of disease mechanisms and progression. In order to identify responsible pathways and genotype/phenotype patterns and establish proof by modeling, a close interdisciplinary approach is needed crossing medical and nonmedical disciplines. First, there is a need for better individualized diagnostics (precision medicine) of underlying disease mechanisms using the new technologies of systems medicine. Second, validated precision T-cell targeted and (stem) cell therapies can be designed on the basis of diagnostic monitoring of molecular pathomechanisms altered by genetic or cellular repair strategies. A number of groups are underway to open the roadblock by precision medicine in clinical and experimental studies. A special focus is given in this issue to stem cell dysfunction in hematologic, cardiac, and neuronal disease based on immune and cardiovascular pathomechanisms.

The current Special Issue will accept original studies, reviews, and technical reports focusing on stem cell/immune cell biology, precision medicine, -omics, animal disease models, molecular diagnostics, biophysics, and imaging written by scientists active in the field of regenerative and precision medicine.

Prof. Dr. Gustav Steinhoff
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

Precision medicine
Systems medicine
Genotype/phenotype signature
Hematological diseases
Cardiovascular diseases
Neuronal diseases
Stem cells
Immune progenitor cells
Autologous cell therapy
Disease modeling
Cardiovascular repair
T-Cell Targeting

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review, Other

2 pages, 176 KiB

Open AccessEditorial

Deciphering the Code: Stem Cell-Immune Function and Cardiac Regeneration

by Gustav Steinhoff

Cells 2021, 10(3), 592; https://doi.org/10.3390/cells10030592 - 8 Mar 2021

Viewed by 1724

Abstract

The development of stem-cell-based and regenerative therapies for cardiovascular and other diseases has faced an unexpected roadblock in clinical translation [...] Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

Research

Jump to: Editorial, Review, Other

15 pages, 7142 KiB

Open AccessArticle

Smart Nanofibers with Natural Extracts Prevent Senescence Patterning in a Dynamic Cell Culture Model of Human Skin

by Emanuela Bellu, Giuseppe Garroni, Sara Cruciani, Francesca Balzano, Diletta Serra, Rosanna Satta, Maria Antonia Montesu, Angela Fadda, Maurizio Mulas, Giorgia Sarais, Pasquale Bandiera, Elena Torreggiani, Fernanda Martini, Mauro Tognon, Carlo Ventura, Jiří Beznoska, Evzen Amler and Margherita Maioli

Cells 2020, 9(12), 2530; https://doi.org/10.3390/cells9122530 - 24 Nov 2020

Cited by 11 | Viewed by 3876 | Correction

Abstract

Natural cosmetic products have recently re-emerged as a novel tool able to counteract skin aging and skin related damages. In addition, recently achieved progress in nanomedicine opens a novel approach yielding from combination of modern nanotechnology with traditional treatment for innovative pharmacotherapeutics. In the present study, we investigated the antiaging effect of a pretreatment with Myrtus communis natural extract combined with a polycaprolactone nanofibrous scaffold (NanoPCL-M) on skin cell populations exposed to UV. We set up a novel model of skin on a bioreactor mimicking a crosstalk between keratinocytes, stem cells and fibroblasts, as in skin. Beta-galactosidase assay, indicating the amount of senescent cells, and viability assay, revealed that fibroblasts and stem cells pretreated with NanoPCL-M and then exposed to UV are superimposable to control cells, untreated and unexposed to UV damage. On the other hand, cells only exposed to UV stress, without NanoPCL-M pretreatment, exhibited a significantly higher yield of senescent elements. Keratinocyte-based 3D structures appeared disjointed after UV-stress, as compared to NanoPCL-M pretreated samples. Gene expression analysis performed on different senescence associated genes, revealed the activation of a molecular program of rejuvenation in stem cells pretreated with NanoPCL-M and then exposed to UV. Altogether, our results highlight a future translational application of NanoPCL-M to prevent skin aging. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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19 pages, 2445 KiB

Open AccessArticle

Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment

by Denise Klatt, Teng-Cheong Ha, Maximilian Schinke, Anton Selich, Anna Lieske, Julia Dahlke, Michael Morgan, Tobias Maetzig and Axel Schambach

Cells 2020, 9(10), 2194; https://doi.org/10.3390/cells9102194 - 29 Sep 2020

Cited by 3 | Viewed by 4009

Abstract

Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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Graphical abstract

18 pages, 3621 KiB

Open AccessArticle

Cardiomyocyte Transplantation after Myocardial Infarction Alters the Immune Response in the Heart

by Praveen Vasudevan, Markus Wolfien, Heiko Lemcke, Cajetan Immanuel Lang, Anna Skorska, Ralf Gaebel, Dirk Koczan, Tobias Lindner, Robby Engelmann, Brigitte Vollmar, Bernd Joachim Krause, Olaf Wolkenhauer, Hermann Lang, Gustav Steinhoff and Robert David

Cells 2020, 9(8), 1825; https://doi.org/10.3390/cells9081825 - 3 Aug 2020

Cited by 11 | Viewed by 4432

Abstract

We investigated the influence of syngeneic cardiomyocyte transplantation after myocardial infarction (MI) on the immune response and cardiac function. Methods and Results: We show for the first time that the immune response is altered as a result of syngeneic neonatal cardiomyocyte transplantation after MI leading to improved cardiac pump function as observed by magnetic resonance imaging in C57BL/6J mice. Interestingly, there was no improvement in the capillary density as well as infarct area as observed by CD31 and Sirius Red staining, respectively. Flow cytometric analysis revealed a significantly different response of monocyte-derived macrophages and regulatory T cells after cell transplantation. Interestingly, the inhibition of monocyte infiltration accompanied by cardiomyocyte transplantation diminished the positive effect of cell transplantation alone. The number of CD68+ macrophages in the remote area of the heart observed after four weeks was also different between the groups. Transcriptome analysis showed several changes in the gene expression involving circadian regulation, mitochondrial metabolism and immune responses after cardiomyocyte transplantation. Conclusion: Our work shows that cardiomyocyte transplantation alters the immune response after myocardial infarction with the recruited monocytes playing a role in the beneficial effect of cell transplantation. It also paves the way for further optimization of the efficacy of cardiomyocyte transplantation and their successful translation in the clinic. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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18 pages, 2732 KiB

Open AccessArticle

Repeated Application of Autologous Bone Marrow-Derived Lineage-Negative Stem/Progenitor Cells—Focus on Immunological Pathways in Patients with ALS

by Bartłomiej Baumert, Anna Sobuś, Monika Gołąb-Janowska, Edyta Paczkowska, Karolina Łuczkowska, Dorota Rogińska, Alicja Zawiślak, Sławomir Milczarek, Bogumiła Osękowska, Wioletta Pawlukowska, Agnieszka Meller, Karolina Machowska-Sempruch, Agnieszka Wełnicka, Krzysztof Safranow, Przemysław Nowacki and Bogusław Machaliński

Cells 2020, 9(8), 1822; https://doi.org/10.3390/cells9081822 - 1 Aug 2020

Cited by 9 | Viewed by 2736

Abstract

Therapeutic interventions in amyotrophic lateral sclerosis (ALS) are still far from satisfying. Immune modulating procedures raise hopes for slowing the disease progression. Stem cell therapies are believed to possess the ability to regulate innate and adaptive immune response and inflammation processes. Hence, three intrathecal administrations of autologous bone marrow-derived lineage-negative (Lin^–) cells were performed every six weeks in 40 sporadic ALS patients. The concentrations of inflammatory-related proteins and expression profiles of selected miRNA in the cerebrospinal fluid (CSF) and plasma at different timepoints post-transplantation were quantified by multiplex Luminex and qRT-PCR. The global gene expression in nucleated blood cells was assessed using the gene microarray technique. According to the ALS Functional Rating Scale (FRSr), the study population was divided into responders (group I, n = 17) and non-responders (group II, n = 23). A thorough analysis of the pro-inflammatory expression profiles, regulated miRNA pathways, and global gene expression profiles at the RNA level revealed the local and systemic effects of Lin^– cell therapy on the immune system of patients with ALS. The autologous application of Lin^– cells in CSF modulates immune processes and might prevent the progression of neurodegeneration. However, further in-depth studies are necessary to confirm the findings, and prolonged intervention is needed to maintain therapeutic effects. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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15 pages, 5535 KiB

Open AccessArticle

Therapy with Cardiomyocytes Derived from Pluripotent Cells in Chronic Chagasic Cardiomyopathy

by Guilherme Visconde Brasil, Danúbia Silva dos Santos, Elias Ataide Mendonça, Fernanda Cristina Paccola Mesquita, Tais Hanae Kasai-Brunswick, Sandro Torrentes da Cunha, Cibele Ferreira Pimentel, Andréia de Vasconcelos-dos-Santos, Rosália Mendez-Otero, Clério Francisco de Azevedo Filho, Regina Coeli dos Santos Goldenberg and Antonio Carlos Campos de Carvalho

Cells 2020, 9(7), 1629; https://doi.org/10.3390/cells9071629 - 7 Jul 2020

Cited by 3 | Viewed by 3070

Abstract

Chagas disease discovered more than a century ago remains an incurable disease. The objective of this work was to investigate the therapeutic potential of cardiomyocytes derived from mouse embryonic stem cells (CM-mESC) in a model of chronic Chagasic cardiomyopathy (CCC). Mouse embryonic stem cells (mESC) were characterized, transduced with luciferase, and submitted to cardiac differentiation. CM-mESC were labeled with superparamagnetic iron oxide particles. To induce CCC, mice were infected with Brazil strain trypomastigotes. At 150 days post-infection (dpi), infected animals were treated with CM-mESC or PBS. Cells were detected by magnetic resonance imaging (MRI) and bioluminescence. Cardiac function was evaluated by MRI and electrocardiogram at 150 and 196 dpi. CCC mice showed significant differences in MRI and ECG parameters compared to non-infected mice. However, no differences were observed in contractile and electrical parameters between cell and PBS injected groups, 45 days after cell transplantation. Cells were detected 24 h after transplantation by MRI. CM-mESC bioluminescence tracking demonstrated over 90% decrease in signal 8 days after treatment. Nevertheless, the Infected + CM-mESC group showed a significant reduction in the percentage of collagen fibers when compared to the Infected + PBS group. In conclusion, CM-mESC therapy was not effective in reversing cardiac functional changes induced by Chagas disease despite some improvement in myocardial fibrosis. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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15 pages, 3152 KiB

Open AccessArticle

[⁶⁸Ga]-NODAGA-RGD Positron Emission Tomography (PET) for Assessment of Post Myocardial Infarction Angiogenesis as a Predictor for Left Ventricular Remodeling in Mice after Cardiac Stem Cell Therapy

by Cajetan Immanuel Lang, Piet Döring, Ralf Gäbel, Praveen Vasudevan, Heiko Lemcke, Paula Müller, Jan Stenzel, Tobias Lindner, Markus Joksch, Jens Kurth, Carina Bergner, Hans-Jürgen Wester, Hüseyin Ince, Gustav Steinhoff, Brigitte Vollmar, Robert David and Bernd Joachim Krause

Cells 2020, 9(6), 1358; https://doi.org/10.3390/cells9061358 - 30 May 2020

Cited by 10 | Viewed by 3146

Abstract

Angiogenesis plays a central role in the healing process following acute myocardial infarction. The PET tracer [⁶⁸Ga]-NODAGA-RGD, which is a ligand for the α_vβ₃ integrin, has been investigated for imaging angiogenesis in the process of healing myocardium in both animal and clinical studies. It’s value as a prognostic marker of functional outcome remains unclear. Therefore, the aim of this work was to establish [⁶⁸Ga]-NODAGA-RGD for imaging angiogenesis in the murine infarct model and evaluate the tracer as a predictor for cardiac remodeling in the context of cardiac stem cell therapy. [⁶⁸Ga]-NODAGA-RGD PET performed seven days after left anterior descending coronary artery (LAD) occlusion in 129S6 mice showed intense tracer accumulation within the infarct region. The specificity was shown in a sub-group of animals by application of the competitive inhibitor cilengitide prior to tracer injection in a subgroup of animals. Myocardial infarction (MI) significantly reduced cardiac function and resulted in pronounced left ventricular remodeling after three weeks, as measured by cardiac MRI in a separate group. Cardiac induced cells (CiC) that were derived from mESC injected intramyocardially in the therapy group significantly improved left ventricular ejection fraction (LVEF). Surprisingly, CiC transplantation resulted in significantly lower tracer accumulation seven days after MI induction. Accordingly, we successfully established the PET tracer [⁶⁸Ga]-NODAGA-RGD for the assessment of α_vβ₃ integrin expression in the healing process after MI in the mouse model. Yet, our results indicate that the mere extent of angiogenesis following MI does not serve as a sufficient prognostic marker for functional outcome. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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15 pages, 3925 KiB

Open AccessArticle

Multi-Omics Analysis of Diabetic Heart Disease in the db/db Model Reveals Potential Targets for Treatment by a Longevity-Associated Gene

by Ashton Faulkner, Zexu Dang, Elisa Avolio, Anita C Thomas, Thomas Batstone, Gavin R Lloyd, Ralf JM Weber, Lukáš Najdekr, Andris Jankevics, Warwick B Dunn, Gaia Spinetti, Carmine Vecchione, Annibale A Puca and Paolo Madeddu

Cells 2020, 9(5), 1283; https://doi.org/10.3390/cells9051283 - 21 May 2020

Cited by 11 | Viewed by 4561

Abstract

Characterisation of animal models of diabetic cardiomyopathy may help unravel new molecular targets for therapy. Long-living individuals are protected from the adverse influence of diabetes on the heart, and the transfer of a longevity-associated variant (LAV) of the human BPIFB4 gene protects cardiac function in the db/db mouse model. This study aimed to determine the effect of LAV-BPIFB4 therapy on the metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptome (next-generation RNAseq) in db/db mice. UHPLC-MS showed that 493 cardiac metabolites were differentially modulated in diabetic compared with non-diabetic mice, mainly related to lipid metabolism. Moreover, only 3 out of 63 metabolites influenced by LAV-BPIFB4 therapy in diabetic hearts showed a reversion from the diabetic towards the non-diabetic phenotype. RNAseq showed 60 genes were differentially expressed in hearts of diabetic and non-diabetic mice. The contrast between LAV-BPIFB4- and vehicle-treated diabetic hearts revealed eight genes differentially expressed, mainly associated with mitochondrial and metabolic function. Bioinformatic analysis indicated that LAV-BPIFB4 re-programmed the heart transcriptome and metabolome rather than reverting it to a non-diabetic phenotype. Beside illustrating global metabolic and expressional changes in diabetic heart, our findings pinpoint subtle changes in mitochondrial-related proteins and lipid metabolism that could contribute to LAV-BPIFB4-induced cardio-protection in a murine model of type-2 diabetes. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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16 pages, 5417 KiB

Open AccessArticle

Integrative Cluster Analysis of Whole Hearts Reveals Proliferative Cardiomyocytes in Adult Mice

by Anne-Marie Galow, Markus Wolfien, Paula Müller, Madeleine Bartsch, Ronald M. Brunner, Andreas Hoeflich, Olaf Wolkenhauer, Robert David and Tom Goldammer

Cells 2020, 9(5), 1144; https://doi.org/10.3390/cells9051144 - 6 May 2020

Cited by 15 | Viewed by 5586

Abstract

The recent development and broad application of sequencing techniques at the single-cell level is generating an unprecedented amount of data. The different techniques have their individual limits, but the datasets also offer unexpected possibilities when utilized collectively. Here, we applied snRNA-seq in whole adult murine hearts from an inbred (C57BL/6NRj) and an outbred (Fzt:DU) mouse strain to directly compare the data with the publicly available scRNA-seq data of the tabula muris project. Explicitly choosing a single-nucleus approach allowed us to pin down the typical heart tissue-specific technical bias, coming up with novel insights on the mammalian heart cell composition. For our integrated dataset, cardiomyocytes, fibroblasts, and endothelial cells constituted the three main cell populations accounting for about 75% of all cells. However, their numbers severely differed between the individual datasets, with cardiomyocyte proportions ranging from about 9% in the tabula muris data to around 23% for our BL6 data, representing the prime example for cell capture technique related bias when using a conventional single-cell approach for these large cells. Most strikingly in our comparison was the discovery of a minor population of cardiomyocytes characterized by proliferation markers that could not be identified by analyzing the datasets individually. It is now widely accepted that the heart has an, albeit very restricted, regenerative potential. However there is still an ongoing debate where new cardiomyocytes arise from. Our findings support the idea that the renewal of the cardiomyocyte pool is driven by cytokinesis of resident cardiomyocytes rather than differentiation of progenitor cells. We thus provide data that can contribute to an understanding of heart cell regeneration, which is a prerequisite for future applications to enhance the process of heart repair. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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Review

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13 pages, 802 KiB

Open AccessFeature PaperReview

mRNA-Enhanced Cell Therapy and Cardiovascular Regeneration

by Palas K. Chanda, Roman Sukhovershin and John P. Cooke

Cells 2021, 10(1), 187; https://doi.org/10.3390/cells10010187 - 19 Jan 2021

Cited by 17 | Viewed by 6818

Abstract

mRNA has emerged as an important biomolecule in the global call for the development of therapies during the COVID-19 pandemic. Synthetic in vitro-transcribed (IVT) mRNA can be engineered to mimic naturally occurring mRNA and can be used as a tool to target “undruggable” diseases. Recent advancement in the field of RNA therapeutics have addressed the challenges inherent to this drug molecule and this approach is now being applied to several therapeutic modalities, from cancer immunotherapy to vaccine development. In this review, we discussed the use of mRNA for stem cell generation or enhancement for the purpose of cardiovascular regeneration. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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Graphical abstract

32 pages, 1421 KiB

Open AccessFeature PaperReview

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

by Stephanie W. Tobin, Faisal J. Alibhai, Richard D. Weisel and Ren-Ke Li

Cells 2020, 9(8), 1894; https://doi.org/10.3390/cells9081894 - 13 Aug 2020

Cited by 14 | Viewed by 5622

Abstract

The importance of the immune system for cardiac repair following myocardial infarction is undeniable; however, the complex nature of immune cell behavior has limited the ability to develop effective therapeutics. This limitation highlights the need for a better understanding of the function of each immune cell population during the inflammatory and resolution phases of cardiac repair. The development of reliable therapies is further complicated by aging, which is associated with a decline in cell and organ function and the onset of cardiovascular and immunological diseases. Aging of the immune system has important consequences on heart function as both chronic cardiac inflammation and an impaired immune response to cardiac injury are observed in older individuals. Several studies have suggested that rejuvenating the aged immune system may be a valid therapeutic candidate to prevent or treat heart disease. Here, we review the basic patterns of immune cell behavior after myocardial infarction and discuss the autonomous and nonautonomous manners of hematopoietic stem cell and immune cell aging. Lastly, we identify prospective therapies that may rejuvenate the aged immune system to improve heart function such as anti-inflammatory and senolytic therapies, bone marrow transplant, niche remodeling and regulation of immune cell differentiation. Full article

(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)

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