Project description:Mesenchymal stem cells (MSCs) have been employed successfully to treat various immune disorders in animal models and clinical settings. Our previous studies have shown that MSCs can become highly immunosuppressive upon stimulation by inflammatory cytokines, an effect exerted through the concerted action of chemokines and nitric oxide (NO). Here, we show that MSCs can also enhance immune responses. This immune-promoting effect occurred when proinflammatory cytokines were inadequate to elicit sufficient NO production. When inducible nitric oxide synthase (iNOS) production was inhibited or genetically ablated, MSCs strongly enhance T-cell proliferation in vitro and the delayed-type hypersensitivity response in vivo. Furthermore, iNOS(-/-) MSCs significantly inhibited melanoma growth. It is likely that in the absence of NO, chemokines act to promote immune responses. Indeed, in CCR5(-/-)CXCR3(-/-) mice, the immune-promoting effect of iNOS(-/-) MSCs is greatly diminished. Thus, NO acts as a switch in MSC-mediated immunomodulation. More importantly, the dual effect on immune reactions was also observed in human MSCs, in which indoleamine 2,3-dioxygenase (IDO) acts as a switch. This study provides novel information about the pathophysiological roles of MSCs.
Project description:Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation-induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self-proliferation, multi-differentiation, injury foci chemotaxis, anti-inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG2+ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double-edged function of MSCs and provide comments on the prospects of these findings.
Project description:Cancer stem cells (CSCs) are a subset of highly tumorigenic cells in tumors. They have enhanced self-renewal properties, are usually chemo-radioresistant, and can promote tumor recurrence and metastasis. They can recruit macrophages into the tumor microenvironment and differentiate them into tumor-associated macrophages (TAMs). TAMs maintain CSC stemness and construct niches that are favorable for CSC survival. However, how CSCs and TAMs interact is not completely understood. An understanding on these mechanisms can provide additional targeting strategies for eliminating CSCs. In this review, we comprehensively summarize the reported mechanisms of crosstalk between CSCs and TAMs and update the related signaling pathways involved in tumor progression. In addition, we discuss potential therapies targeting CSC-TAM interaction, including targeting macrophage recruitment and polarization by CSCs and inhibiting the TAM-induced promotion of CSC stemness. This review also provides the perspective on the major challenge for developing potential therapeutic strategies to overcome CSC-TAM crosstalk.
Project description:Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways. Many comprehensive reviews describing their role in cancer exist, but because most research has been conducted in solid malignancies, evidence in lymphomagenesis is somewhat limited. In this review, we summarize key aspects of sphingolipid biochemistry and discuss their known impact in cancer biology, with a particular focus on lymphomas and possible therapeutical strategies against them.
Project description:Interferon-Stimulated Gene 15 (ISG15) transcript is aberrantly expressed in most human malignancies, suggesting that it has a protumor function. However, at the protein level ISG15 has both protumor and immunomodulatory antitumor functions. Therapeutic strategies to maximize the latter may benefit cancer patients overexpressing the ISG15 pathway.
Project description:Innate lymphoid cells (ILCs) were found to be developmentally related to natural killer (NK) cells. In humans, they are mostly located in "barrier" tissues where they contribute to innate defenses against different pathogens. ILCs are heterogeneous and characterized by a high degree of plasticity. ILC1s are Tbet+, produce interferon gamma and tumor necrosis factor alpha, but, unlike NK cells, are non-cytolytic and are Eomes independent. ILC2 (GATA-3+) secrete type-2 cytokines, while ILC3s secrete interleukin-22 and interleukin-17. The cytokine signatures of ILC subsets mirror those of corresponding helper T-cell subsets. The ILC role in defenses against pathogens is well-documented, while their involvement in tumor defenses is still controversial. Different ILCs have been detected in tumors. In general, the conflicting data reported in different tumors on the role of ILC may reflect the heterogeneity and/or differences in tumor microenvironment. The remarkable plasticity of ILCs suggests new therapeutic approaches to induce differentiation/switch toward ILC subsets more favorable in tumor control.
Project description:Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s.
Project description:BACKGROUND:Fat accumulation commonly occurs in chronically torn rotator cuff muscles, and increased fat within the rotator cuff is correlated with poor clinical outcomes. The extent of lipid deposition is particularly pronounced in injured rotator cuff muscles compared with other commonly injured muscles such as the gastrocnemius. Satellite cells, which are a tissue-resident muscle stem-cell population, can differentiate into fat cells. We hypothesized that satellite cells from the rotator cuff have greater intrinsic adipogenic differentiation potential than do gastrocnemius satellite cells, and this difference is due to variations in epigenetic imprinting between the cells. METHODS:Satellite cells from gastrocnemius and rotator cuff muscles of mice were cultured in adipogenic media, and the capacity to differentiate into mature muscle cells and adipogenic cells was assessed (n ≥ 9 plates per muscle group). We also performed DNA methylation analysis of gastrocnemius and rotator cuff satellite cells to determine whether epigenetic differences were present between the 2 groups (n = 5 mice per group). RESULTS:Compared with the gastrocnemius, satellite cells from the rotator cuff had a 23% reduction in myogenic differentiation and an 87% decrease in the expression of the differentiated muscle cell marker MRF4 (myogenic regulatory factor 4). With respect to adipogenesis, rotator cuff satellite cells had a 4.3-fold increase in adipogenesis, a 12-fold increase in the adipogenic transcription factor PPARγ (peroxisome proliferator-activated receptor gamma), and a 65-fold increase in the adipogenic marker FABP4 (fatty-acid binding protein 4). Epigenetic analysis identified 355 differentially methylated regions of DNA between rotator cuff and gastrocnemius satellite cells, and pathway enrichment analysis suggested that these regions were involved with lipid metabolism and adipogenesis. CONCLUSIONS:Satellite cells from rotator cuff muscles have reduced myogenic and increased adipogenic differentiation potential compared with gastrocnemius muscles. There appears to be a cellular and genetic basis behind the generally poor rates of rotator cuff muscle healing. CLINICAL RELEVANCE:The reduced myogenic and increased adipogenic capacity of rotator cuff satellite cells is consistent with the increased fat content and poor muscle healing rates often observed for chronically torn rotator cuff muscles. For patients undergoing rotator cuff repair, transplantation of autologous satellite cells from other muscles less prone to fatty infiltration may improve clinical outcomes.
Project description:BackgroundBone marrow mesenchymal stem cells (BMSCs) have immense potential in applications for the enhancement of tendon-bone (T-B) healing. Recently, it has been well-reported that skeletal stem cells (SSCs) could induce bone and cartilage regeneration. Therefore, SSCs represent a promising choice for cell-based therapies to improve T-B healing. In this study, we aimed to compare the therapeutic potential of SSCs and BMSCs for tendon-bone healing.MethodsSSCs and BMSCs were isolated by flow cytometry, and their proliferation ability was measured by CCK-8 assay. The osteogenic, chondrogenic, and adipogenic gene expression in cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). C57BL/6 mice underwent unilateral supraspinatus tendon detachment and repair, and the mice were then randomly allocated to 4 groups: control group (tendon-bone interface without any treatment), hydrogel group (administration of blank hydrogel into the tendon-bone interface), hydrogel + BMSCs group (administration of hydrogel with BMSCs into the tendon-bone interface), and hydrogel + SSCs group (administration of hydrogel with SSCs into the tendon-bone interface). Histological staining, Micro-computed tomography (Micro-CT) scanning, biomechanical testing, and qRT-PCR were performed to assay T-B healing at 4 and 8 weeks after surgery.ResultsSSCs showed more cell proportion, exhibited stronger multiplication capacity, and expressed higher osteogenic and chondrogenic markers and lower adipogenic markers than BMSCs. In vivo assay, the SSCs group showed a better-maturated interface which was characterized by richer chondrocytes and more proteoglycan deposition, as well as more newly formed bone at the healing site and increased mechanical properties when compared to other there groups. qRT-PCR analysis revealed that the healing interface in the SSCs group expressed more transcription factors essential for osteogenesis and chondrogenesis than the interfaces in the other groups.ConclusionsOverall, the results demonstrated the superior therapeutic potential of SSCs over BMSCs in tendon-bone healing.The translational potential of this articleThis current study provides valuable insights that SSCs may be a more effective cell therapy for enhancing T-B healing compared to BMSCs.