• Chinese medicine (CM)
• Th17 cell
• coronary heart disease (CHD)
• interleukin-17 (IL-17)
• macrophages

• antimicrobial peptide
• biosafety studies
• cell-based therapy
• genetic engineering
• mesenchymal stromal cells

• Animals
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/cytology
• Wharton Jelly/cytology
• Mice, Inbred C57BL
• Mice
• Mesenchymal Stem Cell Transplantation
• Staphylococcus aureus/drug effects
• Antimicrobial Peptides/metabolism
• Antimicrobial Peptides/genetics
• Female
• Humans
• Disease Models, Animal
• Staphylococcal Infections/therapy

• 075-15-2021-1075 Ministry of Science and Higher Education of the Russian Federation

• atherosclerosis
• cardiovascular diseases
• immune cells
• inflammation
• targeted therapy

• BMSCs
• bone healing
• inflammation
• macrophages
• tissue regeneration

The low healing potential of mature menisci necessitates traditional surgical removal (meniscectomy) to eliminate acute or chronic degenerative tears. However, removal of meniscal tissue is main factor causing osteoarthritis. Adipose tissue-derived regenerative cells (ADRCs), a heterogeneous cell population that includes multipotent adipose-derived stem cells and other progenitor cells, were easily isolated in large amounts from autologous adipose tissue, and same-day processing without culture or expansion was possible. This study investigated the regenerative potential of autologous ADRCs for use in meniscus defects.

In 10- to 12-week-old male SD rat partial meniscectomy model, an atelocollagen sponge scaffold without or with ADRCs (5.0 × 10⁵ cells) was injected into each meniscus defect. Reconstructed menisci were subjected to histologic, and dynamic mechanical analyses.

After 12 weeks, areas of regenerated meniscal tissue in the atelocollagen sponge scaffold in rats with ADRCs (64.54 ± 0.52%, P < 0.05, n = 10) were larger than in those without injection (57.96 ± 0.45%). ADRCs were shown capable of differentiating chondrocyte-like cells and meniscal tissue components such as type II collagen. Higher elastic moduli and lower fluid permeability of regenerated meniscal tissue demonstrated a favorable structure-function relationship required for native menisci, most likely in association with micron-scale porosity, with the lowest level for tissue integrity possibly reproducible.

This is the first report of meniscus regeneration induced by injection of ADRCs. The results indicate that ADRCs will be useful in future clinical cell-based therapy strategies, including as a cell source for reconstruction of damaged knee menisci.

• Cardiac regeneration
• Cardiac repair
• Mesenchymal stem cell
• Myocardial ischemia
• Paracrine
• Secreted

• Humans
• Mesenchymal Stem Cell Transplantation
• Paracrine Communication
• Cardiovascular Diseases/therapy
• Stroke Volume
• Myocardial Infarction/therapy
• Ventricular Function, Left

• Austrian Science Fund
• The University of Newcastle (Australia)

Background: Nanofat grafting (NG) is a simple and cost-effective method of lipoaspirates with inter-syringe passages, to produce stromal vascular fraction (SVF) and isolate adipose-derived stem cells (ASCs). This represents a tremendous interest in the future clinical needs of tissue engineering. In this study, we optimized the NG technique to increase the yield of ASC extractions.

Methods: We analyzed three groups of SVF obtained by 20, 30, and 40 inter-syringe passages. The control group was an SVF obtained by enzymatic digestion with Celase. We studied their cell composition by flow cytometry, observed their architecture by confocal microscopy, and observed immunomodulatory properties of the ASCs from each of the SVFs by measuring inflammatory markers of macrophages obtained by an ASC monocyte co-culture.

Results: We have established the first cell mapping of the stromal vascular fraction of adipose tissue. The results showed that SVF obtained by 20 inter-syringe passages contains more statistically significant total cells, more cells expressing the ASC phenotype, more endothelial cells, and produces more CFU-F than the SVF obtained by 30 and 40 passages and by enzymatic digestion. Confocal microscopy showed the presence of residual adipocytes in SVF obtained by inter-syringe passages but not by enzymatic digestion. The functional study indicates an orientation toward a more anti-inflammatory profile and homogenization of their immunomodulatory properties.

Conclusion: This study places mechanically dissociated SVF in the center of approaches to easily extract ASCs and a wide variety and number of other progenitor cells, immediately available in a clinical setting to provide both the amount and quality of cells required for decellularized tissues.

Mesenchymal stromal cell (MSC)-based therapies for inflammatory diseases rely mainly on the paracrine ability to modulate the activity of macrophages. Despite recent advances, there is scarce information regarding changes of the secretome content attributed to physiomimetic cultures and, especially, how secretome content influence on macrophage activity for therapy. hLMSCs from human donors were cultured on devices developed in house that enabled lung-mimetic strain. hLMSC secretome was analyzed for typical cytokines, chemokines and growth factors. RNA was analyzed for the gene expression of CTGF and CYR61. Human monocytes were differentiated to macrophages and assessed for their phagocytic capacity and for M1/M2 subtypes by the analysis of typical cell surface markers in the presence of hLMSC secretome. CTGF and CYR61 displayed a marked reduction when cultured in lung-derived hydrogels (L-Hydrogels). The secretome showed that lung-derived scaffolds had a distinct secretion while there was a large overlap between L-Hydrogel and the conventionally (2D) cultured samples. Additionally, secretome from L-Scaffold showed an HGF increase, while IL-6 and TNF-α decreased in lung-mimetic environments. Similarly, phagocytosis decreased in a lung-mimetic environment. L-Scaffold showed a decrease of M1 population while stretch upregulated M2b subpopulations. In summary, mechanical features of the lung ECM and stretch orchestrate anti-inflammatory and immunosuppressive outcomes of hLMSCs.

• MSC-based therapy
• lung physiomimetic culture
• macrophages
• preconditioning

The immunomodulatory effects of mesenchymal stem cells (MSCs) on macrophages have been reported, however, the underlying mechanism remains unknown. Therefore, this study aimed to investigate the anti-inflammatory effects of MSCs on lipopolysaccharide (LPS)-stimulated macrophages and the subsequent downregulation of their inflammatory mediators. Macrophages were treated with conditioned media from MSCs, without a subsequent change of MSCs responding to the inflammation state. This study also evaluated whether the interleukin (IL) 4 stimulation of MSCs can improve their anti-inflammatory effects. Results demonstrated that the MSC-conditioned medium (MSC-CM) stimulated with IL4 significantly inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression of LPS-activated macrophages. MSC-CM treatment inhibited the mRNA transcription of the cytokines IL1β and IL6, the chemokines C–C motif ligand (CCL) 2, CCL3, CCL4, and CCL5, and the chemokine receptors CCR2 and CCR5, in LPS-stimulated macrophages. As revealed through western blot and immunofluorescence analyses, the phosphorylation of p38, JNK, and ERK MAPKs, as well as phosphorylation of NF-κB in stimulated macrophages, were also inhibited by the MSC-CM. Further, more potent anti-inflammatory effects were observed with the IL4-stimulated cells, compared with those observed with the non-stimulated cells. The MSC-CM demonstrated a potent anti-inflammatory effect on LPS-activated macrophages, while the IL4 stimulation improved this effect. These findings indicate that MSCs could exert anti-inflammatory effects on macrophages, and may be considered as a therapeutic agent in inflammation treatment.

Mesenchymal stem cells (MSCs) are the member of multipotency stem cells, which possess the capacity for self-renewal and multi-directional differentiation, and have several characteristics, including multi-lineage differentiation potential and immune regulation, which make them a promising source for cell therapy in inflammation, immune diseases, and organ transplantation. In recent years, MSCs have been described as a novel therapeutic strategy for the treatment of cardiovascular diseases because they are potent modulators of immune system with the ability to modulating immune cell subsets, coordinating local and systemic innate and adaptive immune responses, thereby enabling the formation of a stable inflammatory microenvironment in damaged cardiac tissues. In this review, the immunoregulatory characteristics and potential mechanisms of MSCs are sorted out, the effect of these MSCs on immune cells is emphasized, and finally the application of this mechanism in the treatment of cardiovascular diseases is described to provide help for clinical application.

• cardiovascular disease
• immune cells
• immune regulation
• inflammation
• mesenchymal stem cells

• atherosclerosis
• immunomodulation
• inflammation
• mesenchymal stem cell
• stem cell science
• therapeutics

• C-X-C motif chemokine ligand 12 (CXCL12)
• Cytokine
• Macrophage
• Mesenchymal stem cells (MSCs)
• Phagocytosis
• Tumor microenvironment

• Animals
• Carcinogenesis/immunology
• Carcinogenesis/pathology
• Cells, Cultured
• Chemokine CXCL12/immunology
• Female
• Macrophage Activation
• Macrophages/immunology
• Macrophages/pathology
• Mesenchymal Stem Cells/immunology
• Mesenchymal Stem Cells/pathology
• Mice, Inbred BALB C
• Neoplasms/immunology
• Neoplasms/pathology
• Mice

• University of Tehran

Macrophages are involved in almost every aspect of biological systems and include development, homeostasis and repair. Mesenchymal stem cells (MSCs) have good clinical application prospects due to their ability to regulate adaptive and innate immune cells, particularly macrophages, and they have been used successfully for many immune disorders, including inflammatory bowel disease (IBD), acute lung injury, and wound healing, which have been reported as macrophage-mediated disorders. In the present review, we focus on the interaction between MSCs and macrophages and summarize their methods of interaction and communication, such as cell-to-cell contact, soluble factor secretion, and organelle transfer. In addition, we discuss the roles of MSC-macrophage crosstalk in the development of disease and maintenance of homeostasis of inflammatory microenvironments. Finally, we provide optimal strategies for applications in immune-related disease treatments.

• clinic therapy
• homeostasis
• macrophage
• mesenchymal stem cells
• microenvironment

Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.

• macrophage
• stem cell
• stem cell niche
• tissue regeneration

• Type 1 Diabetes
• autoimmune disorder
• immunomodulation
• review.
• stem cells
• treatment

• Adipose derived stem cell
• Angiogenesis
• Cardiac adipose tissue
• Cardiac repair
• Inflammation

Cardiac remodeling describes a series of structural and functional changes in the heart after myocardial infarction (MI). Adverse post-MI cardiac remodeling directly jeopardizes the recovery of cardiac functions and the survival rate in MI patients. Several classes of drugs are proven to be useful to reduce the mortality of MI patients. However, it is an ongoing challenge to prevent the adverse effects of cardiac remodeling. The present review aims to identify the pharmacological therapies from the existing clinical drugs for the treatment of adverse post-MI cardiac remodeling. Post-MI cardiac remodeling is a complex process involving ischemia/reperfusion, inflammation, cell death, and deposition of extracellular matrix (ECM). Thus, the present review included two parts: (1) to examine the basic pathophysiology in the cardiovascular system and the molecular basis of cardiac remodeling and (2) to identify the pathological aspects of cardiac remodeling and the potential of the existing pharmacotherapies. Ultimately, the present review highlights drug repositioning as a strategy to discover effective therapies from the existing drugs against post-MI cardiac remodeling.

We intended to explore the cellular interaction between mesenchymal stem cells (MSCs) and injured endothelial cells leading to macrophage alternative polarization in healing kidney ischemic reperfusion injury. In vivo, the amounts of recruited macrophages were significantly mitigated by MSCs in the injured tissues, especially in the group using hematopoietic cell E- and L-selectin ligand (HCELL)-positive MSCs. Compared to controls, MSCs also enhanced expression of CD206 and CD163, which was further enhanced by HCELL expression. In vitro, analysis of cytokines involving macrophage polarization showed IL-13 rather than IL-4 from MSCs agreed with expression of macrophage CD206 in the presence of hypoxic endothelial cells. Among them, HCELL-positive MSCs in contact with hypoxic endothelial cells produced the greatest response, which were reduced without HCELL or using a transwell to prevent cell contact. With blockade of the respective cytokine, downregulated MSCs secretion of IL-13 and CD206 expression were observed using inhibitors of IFN-γ and TNF-α, but not using those of TGF-β and NO. With IFN-γ and TNF-α, MSCs IL-13 secretion and CD206 expression were upregulated. In conclusion, hypoxia induces endothelial cells producing multiple cytokines. Among them, IFN-γ and TNF-α that stimulate MSCs to secrete IL-13 but not IL-4, leading to alternative polarization.

• alternative macrophage polarization
• hematopoietic cell E- and L-selectin ligand
• hypoxic endothelial cells
• mesenchymal stem cells

Mesenchymal stromal cells (MSC) have immunomodulatory effects impacting macrophages, promoting polarisation towards a reparative phenotype. CCL2 is a potent cytokine involved in the recruitment of macrophages. We hypothesised that MSC derived CCL2 may be involved in the MSC therapeutic effect by facilitating macrophage repolarisation. To further delineate this mechanism, MSC isolated from CCL2 deficient mice (MSC-KO) were applied to excisional wounds in wild-type (WT) mice. CCL2 deficiency in MSC completely abrogated the therapeutic response compared to MSC-WT. MSC-KO were unable to repolarise macrophages to the same extent as WT and this was accompanied by a reduced angiogenesis and re-epithelialisation of the wounds at day 10. This study demonstrates that MSC derived CCL2 is required for MSC induced accelerated wound healing. The role of CCL2 in the interaction between MSC and Macrophages has not been previously demonstrated in accelerated wound healing. CCL2 has a potent effect on the ability to reduce the inflammatory response through local recruitment of macrophages. This research highlights CCL2 as a possible target for augmentation of MSC therapy to enhance therapeutic potential.

Mesenchymal stem cells (MSCs) appear to be a potential vehicle for anticancer drugs due to their excellent tumor tropism ability. However, the interactions between MSCs and hepatocellular carcinoma (HCC) are quite controversial and the underlying mechanisms are ambiguous. In this study, an investigation was conducted into the effect of human MSCs (hMSCs) on tumor proliferation and metastasis both in xenograft and orthotopic models. It was discovered that hMSCs could promote tumor growth though activating mitogen-activated protein kinase (MAPK) signaling pathway and promote metastasis by epithelial mesenchymal transition (EMT) in vivo. To test whether hMSCs could induce immunosuppressive effects, the expression of the Natural killer (NK) cell marker CD56 was measured by immunohistochemical staining and the expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured by qRT-PCR. It was found out that CD56 expression significantly decreased, while TNF-α and IL-6 expression increased in the hMSCs-treated tissues. Mechanistically, RNA sequencing was performed, which led to a discovery that integrin α5 (ITGA5) was over-expressed in hMSCs-treated HCC. ITGA5 siRNAs blocked the hMSCs-induced migration and invasion of HCC, while over-expression of ITGA5 promoted the migration and invasion ability in HCC-hMSCs, indicating that the expression of ITGA5 is associated with hMSCs-induced tumor metastasis. These findings suggest that hMSCs may play a vital role in HCC proliferation and metastasis and could be identified as a putative therapeutic target in HCC.

• Calcification
• Hyperlipidemia
• Immunomodulation
• Small extracellular vesicles (sEVs)
• Tissue regeneration
• Vascular grafts

Placental mesenchymal stem cells from maternal decidua basalis tissue (DBMSCs) are promising cells for tissue repair because of their multilineage differentiation and ability to protect endothelial cells from injury. Here, we examined DBMSC interaction with macrophages and whether this interaction could modulate the characteristics and functions of these macrophages. We induced monocytes to differentiate into M1-like macrophages in the presence of DBMSCs. DBMSC effects on differentiation were evaluated using microscopy, flow cytometry, and ELISA. DBMSC effects on M1-like macrophage induction of T cell function were also examined. The culture of DBMSCs with monocytes did not inhibit monocyte differentiation into M1-like inflammatory macrophages. This was confirmed by the morphological appearance of M1-like macrophages, increased expression of inflammatory molecules, and reduced expression of anti-inflammatory molecules. In addition, DBMSCs did not interfere with M1-like macrophage phagocytic activity; rather, they induced stimulatory effects of M1-like macrophages on CD4⁺ T cell proliferation and subsequent secretion of inflammatory molecules by T cells. We showed that DBMSCs enhanced the differentiation of M1-like inflammatory macrophages, which function as antitumor cells. Therefore, our findings suggest that DBMSCs are inflammatory cells that could be useful in cancer treatment via the enhancement of M1- like macrophages.

• M1 macrophages
• inflammation
• inflammatory cells
• placental stem cells

• Adult
• Antigens, CD/metabolism
• Biomarkers/metabolism
• Cell Differentiation
• Cell Membrane/metabolism
• Cell Proliferation
• Cells, Cultured
• Cytokines/metabolism
• Decidua/cytology
• Female
• Humans
• Inflammation/pathology
• Macrophages/metabolism
• Macrophages/pathology
• Mesenchymal Stem Cells/cytology
• Phagocytosis
• T-Lymphocytes/cytology

• bioreactors
• cell- and tissue-based therapy
• mesenchymal stromal cells
• quality control

Blast concussions are a common injury sustained in military combat today. Inflammation due to microglial polarization can drive the development of visual defects following blast injuries. In this study, we assessed whether anti-inflammatory factors released by the mesenchymal stem cells derived from adipose tissue (adipose stem cells, ASC) can limit retinal tissue damage and improve visual function in a mouse model of visual deficits following mild traumatic brain injury. We show that intravitreal injection of 1 μL of ASC concentrated conditioned medium from cells pre-stimulated with inflammatory cytokines (ASC-CCM) mitigates loss of visual acuity and contrast sensitivity four weeks post blast injury. Moreover, blast mice showed increased retinal expression of genes associated with microglial activation and inflammation by molecular analyses, retinal glial fibrillary acidic protein (GFAP) immunoreactivity, and increased loss of ganglion cells. Interestingly, blast mice that received ASC-CCM improved in all parameters above. In vitro, ASC-CCM not only suppressed microglial activation but also protected against Tumor necrosis alpha (TNFα) induced endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrate TSG-6 is highly expressed in ASC-CCM from cells pre-stimulated with TNFα and IFNγ but not from unstimulated cells. Our findings suggest that ASC-CCM mitigates visual deficits of the blast injury through their anti-inflammatory properties on activated pro-inflammatory microglia and endothelial cells. A regenerative therapy for immediate delivery at the time of injury may provide a practical and cost-effective solution against the traumatic effects of blast injuries to the retina.

• TBI
• TIMP1
• TSG6
• adult stem cells
• microglia
• oxidative stress
• retinal ganglion cells
• trans-endothelial electrical resistance

Inflammatory breast cancer (IBC) is a unique and deadly disease with unknown drivers. We hypothesized the inflammatory environment contributes to the IBC phenotype. We used an in vitro co-culture system to investigate interactions between normal and polarized macrophages (RAW 264.7 cell line), bone-marrow derived mesenchymal stem cells (MSCs), and IBC cells (SUM 149 and MDA-IBC3). We used an in vivo model that reproduces the IBC phenotype by co-injecting IBC cells with MSCs into the mammary fat pad. Mice were then treated with a macrophage recruitment inhibitor, anti-CSF1. MSC and macrophages grown in co-culture produced higher levels of pro-tumor properties such as enhanced migration and elevated IL-6 secretion. IBC cells co-cultured with educated MSCs also displayed enhanced invasion and mammosphere formation and blocked by anti-IL-6 and statin treatment. The treatment of mice co-injected with IBC cells and MSCs with anti-CSF1 inhibited tumor associated macrophages and inhibited pSTAT3 expression in tumor cells. Anti-CSF1 treated mice also exhibited reduced tumor growth, skin invasion, and local recurrence. Herein we demonstrate reciprocal tumor interactions through IL-6 with cells found in the IBC microenvironment. Our results suggest IL-6 is a mediator of these tumor promoting influences and is important for the IBC induced migration of MSCs.

• IL-6
• inflammatory breast cancer
• macrophages
• mesenchymal stem cells
• statins

• Bone regeneration
• Fracture repair
• Inflammaging
• Macrophages
• Osteoporosis
• Senescence

• Aging/immunology
• Aging/metabolism
• Bone Regeneration/immunology
• Cellular Senescence
• Fracture Healing/immunology
• Homeostasis
• Humans
• Inflammation
• Macrophage Colony-Stimulating Factor/metabolism
• Macrophages/immunology
• Macrophages/metabolism
• Osteoclasts/metabolism
• Osteoclasts/physiology
• Osteoporosis/immunology
• Receptor, Macrophage Colony-Stimulating Factor/metabolism

• immunology
• inflammation
• polymeric scaffolds
• tissue engineering

• adipose tissue‐derived mesenchymal stem cells
• allogeneic origin
• myocardial infarction
• myocardial perfusion
• vascular density

• Adipose Tissue/cytology
• Angiogenic Proteins/metabolism
• Animals
• Cells, Cultured
• Computed Tomography Angiography
• Coronary Angiography/methods
• Coronary Circulation
• Cytokines/metabolism
• Disease Models, Animal
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Magnetic Resonance Imaging
• Male
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Multidetector Computed Tomography
• Myocardial Infarction/diagnostic imaging
• Myocardial Infarction/metabolism
• Myocardial Infarction/physiopathology
• Myocardial Infarction/surgery
• Myocardium/metabolism
• Myocardium/pathology
• Neovascularization, Physiologic
• Perfusion Imaging/methods
• Recovery of Function
• Regeneration
• Sus scrofa
• Time Factors
• Transfection
• Transplantation, Homologous
• Ventricular Dysfunction, Left/diagnostic imaging
• Ventricular Dysfunction, Left/metabolism
• Ventricular Dysfunction, Left/physiopathology
• Ventricular Dysfunction, Left/surgery
• Ventricular Function, Left

• heart failure
• inflammation
• mesenchymal stromal/stem cells
• toll-like receptor-4

The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

• Immunohomeostasis
• Immunoprotection
• Immunoregeneration
• Inflammation
• Mesenchymal stem cells
• IMT504

• adipose-derived stem cells
• cell-mediated therapy
• ischemic injury
• macrophages
• peripheral artery disease
• skeletal muscle regeneration

Macrophages and Wnt proteins (Wnts) are independently involved in cardiac development, response to cardiac injury, and repair. However, the role of macrophage‐derived Wnts in the healing and repair of myocardial infarction (MI) is unknown. We sought to determine the role of macrophage Wnts in infarct repair.

We show that the Wnt pathway is activated after MI in mice. Furthermore, we demonstrate that isolated infarct macrophages express distinct Wnt pathway components and are a source of noncanonical Wnts after MI. To determine the effect of macrophage Wnts on cardiac repair, we evaluated mice lacking the essential Wnt transporter Wntless (Wls) in myeloid cells. Significantly, Wntless‐deficient macrophages presented a unique subset of M2‐like macrophages with anti‐inflammatory, reparative, and angiogenic properties. Serial echocardiography studies revealed that mice lacking macrophage Wnt secretion showed improved function and less remodeling 30 days after MI. Finally, mice lacking macrophage‐Wntless had increased vascularization near the infarct site compared with controls.

Macrophage‐derived Wnts are implicated in adverse cardiac remodeling and dysfunction after MI. Together, macrophage Wnts could be a new therapeutic target to improve infarct healing and repair.

• Wnt signaling
• macrophage
• myocardial infarction
• remodeling

• Heme oxygenase 1
• Hemin
• Inflammation
• Macrophage
• Myocardial infarction
• Targeted carrier

Cardiosphere-derived cells (CDCs), one of the promising stem cell sources for myocardial repair, have been tested in clinical trials and resulted in beneficial effects; however, the relevant mechanisms are not fully understood. In this study, we examined the hypothesis that CDCs favor heart repair by switching the macrophages from a pro-inflammatory phenotype (M1) into a regulatory anti-inflammatory phenotype (M2). Macrophages from mice were cultured with CDCs-conditioned medium or with fibroblasts-conditioned medium as a control. Immunostaining showed that CDCs-conditioned medium significantly enhanced the expression of CD206 (a marker for M2 macrophages), but decreased the expression of CD86 (a marker for M1 macrophages) 3 days after culture. For animal studies, we used an acute myocardial infarction model of mice. We injected CDCs, fibroblasts, or saline only into the border zone of infarction. Then we collected the heart tissues for histological analysis 5 and 14 days after treatment. Compared with control animals, CDCs treatment significantly decreased M1 macrophages and neutrophils but increased M2 macrophages in the infarcted heart. Furthermore, CDCs-treated mice had reduced infarct size and fewer apoptotic cells compared to the controls. Our data suggest that CDCs facilitate heart repair by modulating M1/M2 macrophage polarization and neutrophil recruitment, which may provide a new insight into the mechanisms of stem cell-based myocardial repair.

• Animals
• B7-2 Antigen/metabolism
• Cell Differentiation
• Cells, Cultured
• Culture Media, Conditioned/pharmacology
• Disease Models, Animal
• Fibroblasts/cytology
• Fibroblasts/metabolism
• Heart/physiology
• Lectins, C-Type/metabolism
• Macrophages/cytology
• Macrophages/drug effects
• Macrophages/metabolism
• Male
• Mannose Receptor
• Mannose-Binding Lectins/metabolism
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction/pathology
• Myocardial Infarction/therapy
• Myocardium/metabolism
• Myocardium/pathology
• Neutrophil Infiltration
• Neutrophils/cytology
• Neutrophils/metabolism
• Receptors, Cell Surface/metabolism
• Regeneration

• This study was partially supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology, Japan, the Ministry of Higher Education, Egypt and partially supported by the National Natural Science Foundation of China

Osteoarthritis (OA) is associated with chronic inflammation, and mesenchymal stromal cells (MSCs) have been shown to provide pain relief and reparative effects in clinical investigations. MSCs are often delivered with hyaluronic acid (HA), although the combined mechanism of action is not fully understood; we thus investigated the immunomodulatory effects of combining MSCs with different molecular weights (MW) of HA.

HAs with MWs of 1.6 MDa (hHA), 150 kDa or 7.5 kDa, were added to MSCs alone or MSC-immune cell co-cultures. Gene expression analyses, flow cytometry and cytokine measurements were assessed to determine the effect of HAs on the MSC interactions with immune cells.

MSCs in the presence of HAs, in both normal and lymphocyte-conditioned medium, showed negligible changes in gene expression. While addition of hHA resulted in increased proliferation of activated lymphocytes, both in the presence and absence of MSCs, the overall combined effect was a more regulated, homeostatic one; this was supported by higher ratios of secreted IL10/IFNγ and IL10/IL2, in lymphocyte cultures, than with lower MW HAs or no HA, both in the presence and absence of MSCs. In addition, examination of monocyte-derived macrophages showed an increased M2 macrophage frequency (CD14+CD163+CD206+) in the presence of hHA, both with and without MSCs.

hHA produces a less pro-inflammatory environment than lower MW HAs. Moreover, combining hHA with MSCs has an additive effect on the MSC-mediated immunomodulation, suggestive of a more potent combination treatment modality for OA.

• Cell Proliferation
• Cells, Cultured
• Coculture Techniques
• Drug Evaluation, Preclinical
• Gene Expression/drug effects
• Humans
• Hyaluronic Acid/chemistry
• Hyaluronic Acid/pharmacology
• Immunologic Factors/chemistry
• Immunologic Factors/pharmacology
• Immunomodulation
• Macrophages/physiology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/physiology
• Molecular Weight
• T-Lymphocytes, Helper-Inducer/physiology
• T-Lymphocytes, Regulatory/physiology

• haematology
• immunology
• neurobiology
• regulation
• stem cells
• tissue regeneration
• tumour vaccination

• 97922 Wellcome Trust
• R01 DK069370 NIDDK NIH HHS
• UH3 TR000880 NCATS NIH HHS
• UH3 TR000884 NCATS NIH HHS