Major depressive disorder (MDD) is a severe, and often treatment-resistant, psychiatric disorder. Mesenchymal stem cell-derived exosomes have been shown to be neuroprotective. Here we employed adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) as a novel therapeutic approach for depressive-like behavior in mice and explored the underlying mechanisms.

ADSC-Exos were administered intranasally to mice subjected to chronic restraint stress to assess behavioral changes and neuroprotection in terms of apoptosis, AMPK-mTOR signaling, and NLRP3 pathway activation by western blotting, microglial activation by immunofluorescence, and changes in serum inflammatory factors by ELISA. The effects of ADSC-Exos were also studied in vitro in HT22 cells.

ADSC-Exos significantly improved depressive-like behavior, anxiety-like behavior, and cognitive function in mice. ADSC-Exos had significant neuroprotective effects, including reducing neuronal apoptosis and promoting autophagy by activating AMPK-mTOR signaling, ultimately reducing neuroinflammation. In vitro, ADSC-Exos inhibited corticosterone-induced apoptosis, activated autophagy in an AMPK pathway-dependent manner, and inhibited NLRP3 inflammasome activation.

ADSC-Exos may be a potential treatment for MDD by alleviating depressive-like behaviors and protecting against tissue injury, possibly through activation of AMPK-mTOR signaling and inhibition of NLRP3 inflammasome-mediated neuroinflammation.

Exosomes are small extracellular vesicles produced by most cell types and contain proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, and DNA) that can be released by donor cells to influence the function of recipient cells. Skin photoaging is the premature aging of skin structures caused by prolonged exposure to ultraviolet (UV), as demonstrated by depigmentation, roughness, rhytides, elastosis, and precancerous alterations. Exosomes are associated with aging processes such as oxidative damage, inflammation, and senescence. Exosomes' anti-aging properties have been linked to various in vitro and preclinical investigations. There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, skin tissue via a variety of mechanisms, including reduced matrix metalloproteinase (MMP) expression, increased collagen and elastin production, and modulation of intracellular signaling pathways and intercellular communication. These findings suggest the therapeutic potential of exosomes in skin aging. This review provides information on the molecular mechanisms and consequences of exosome anti-aging.

Trauma injuries represent a significant public health burden worldwide, often leading to long-term disability and reduced quality of life. This review provides a comprehensive overview of the therapeutic potential of stem cells and cell products for traumatic injuries. The extraordinary characteristics of stem cells, such as self-renewal and transdifferentiation, make them definitive candidates for tissue regeneration. Mesenchymal stem cells (MSCs), neural stem cells (NSCs), and hematopoietic stem cells (HSCs) have been tested in preclinical studies for treating distinct traumatic injuries. Stem cell mechanisms of action are addressed through paracrine signaling, immunomodulation, differentiation, and neuroprotection. Cell products such as conditioned media, exosomes, and secretomes offer cell-free resources, thereby avoiding the risks of live cell transplantation. Clinical trials have reported many effective outcomes; however, variability exists across trauma types. Some challenges include tumorigenicity, standardized protocols, and regulatory issues. Collaboration and interdisciplinary research are being conducted to harness stem cells and products for trauma treatment. This emerging field is promising for improving patient recovery and quality of life after traumatic injuries.

IFN-γ and TNF-α are two vital inflammatory factors elevated aberrantly in many diseases. Such an inflammatory microenvironment is detrimental to residual cells such as mesenchymal stem cells (MSCs), yet the precise mechanisms are not fully understood. IFN-γ and TNF-α have distinct effects on the immunoregulatory properties of MSCs, and they have been proposed as optimal priming factors to enhance the immunosuppressive capacity of engineered MSCs. Thus, the overall effects of IFN-γ and/or TNF-α exposure on MSCs needs to be elucidated. Here, it is found that IFN-γ and TNF-α synergistically induce cell death of MSCs via necroptosis. When MSCs are exposed to both IFN-γ and TNF-α, their morphological features and biological functions are impaired. Mechanistically revealed by RNA-Sequencing, the injured MSCs undergo a unique cell death process, namely necroptosis. Compared with controls, IFN-γ synergized with TNF-α to increase the expression of RIPK1, RIPK3, MLKL, and all other genes associated with necroptosis. Rescue experiments further demonstrate that this process can be reversed by RIPK3 and MLKL inhibitors but not by the RIPK1 inhibitor, suggesting a RIPK1-independent pathway. Collectively, this study discloses an inflammatory injury mechanism of MSCs, which may shed new light on revealing the MSCs deficits in many inflammatory diseases with expectations to inspire potential targeted therapies. In addition, inflammatory impairment should be taken into consideration when delivering cell therapy based on MSCs primed with IFN-γ and TNF-α.

Herpes simplex keratitis (HSK) is a leading cause of corneal blindness globally, primarily resulting from herpes simplex virus type 1 (HSV-1) infection. HSK can cause pervasive and irreversible corneal nerve damage, leading to decreased corneal sensitivity and vision loss. Interleukin (IL)-33, a multifunctional cytokine, plays an important role in immune and inflammatory responses. However, the effects of IL-33 on nerve damage associated with HSK and the underlying mechanisms remain poorly understood. In this study, we first evaluated the effects of IL-33 on the severity of HSK and corneal nerve damage in a mouse model of HSK. The mechanisms of IL-33 on the production of neuroprotective factors by corneal epithelial cells (HCE-Ts) were investigated in an HSV-1 infection model in vitro. Additionally, the role and mechanism of IL-33 in regulating macrophage polarization for neuroprotection were investigated through in vitro co-culture experiments. The results indicated that IL-33 reduced the severity of HSK and protected corneal nerves in HSK mouse model. Mechanistically, IL-33 promoted the production of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) via activation of the GSK3β/β-catenin signaling pathway in corneal epithelial cells. Furthermore, IL-33 promoted M2 macrophage polarization through activation of the JAK2/STAT6 pathway, which in turn attenuated inflammatory responses and reduced neuronal apoptosis. These findings reveal the neuroprotective mechanisms of IL-33 in HSK and offer new insights for further research and treatment of HSK.

As mechanosensory cells, periodontal ligament stem cells (PDLSCs) react to mechanical force through proliferative, immunomodulatory, and regenerative actions that promote bone deposition. This study aimed to investigate how biomechanical compressive forces modulate PDLSCs' self-tolerance to proinflammatory responses.

PDLSCs were cultured and characterized using flow cytometry. Intermittent compressive force (ICF) was applied to the cells using a computerized-controlled apparatus, with a force of 1.5 g/cm² at 0.23 Hz for 24 hours. TLR4 activation was induced using lipopolysaccharides (LPS) from P. gingivalis, in the presence or absence of ICF. Pathway inhibitors targeting TGF-β receptor type 1, Rho kinase, and NF-kB were applied to investigate the signaling pathways. Pro-inflammatory cytokine levels were measured using qPCR and ELISA. Western blotting was performed to assess the protein expression of TLR4 and TGF-β1. Immunofluorescence staining was used to localize TLR4. Osteogenic differentiation and IDO enzymatic activity were assessed.

Our results showed that PDLSCs primed with ICF developed tolerance to self-inflammatory responses when exposed to LPS, as indicated by reduced levels of inflammatory factors such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. This tolerance, specific to ICF-primed PDLSCs, was partially mediated by the NF-kB p65 signaling pathway. Additionally, ICF enhanced PDLSC immunosuppressive properties and restored osteogenic differentiation, which had been delayed by LPS/TLR4 activation. Notably, TLR4 responded directly to ICF stimulation.

This study demonstrated that priming inflamed PDLSCs with biomechanical compressive force induces a tolerance effect against infection-induced inflammation, promoting bone regeneration.

This study underscores the critical role of tolerance mechanisms in maintaining PDLSCs homeostasis, highlights the intricate interplay between biomechanical forces and immune modulation, and provides new insights into manipulating stem cells and developing therapeutic strategies to enhance bone and tissue regeneration in immune-related disorders, particularly periodontal disease.

To evaluate the feasibility, safety and efficacy of the cutaneous application of Bioengineered Artificial Mesenchymal Sheet (BAMS) in venous leg ulcers (VLUs) versus conventional treatment.

This protocol is based on the design of a Phase I/II, multicenter, randomized, controlled, open-label clinical trial investigating the application of a biological dressing supplemented with mesenchymal stem cells (NCT05962931). The clinical trial is being conducted in 2 primary care units within the Granada Metropolitan Health District. A total of 20 patients with VLUs are being randomized (1:1) into 2 intervention arms: a control group and a treatment group. The intervention in the treatment group consists of the local application of 4 doses of BAMS, administered once per week, while the control group receives conventional therapy. Feasibility will be assessed based on the ability to complete the administration of 4 doses in at least 80% of the patients in the treatment group. Safety will be evaluated by analyzing the incidence of adverse effects and serious adverse effects. Efficacy will be assessed in terms of the percentage of wound closure (measured by wound area reduction), macroscopic assessment of the lesion (visual macroscopic analysis and RESVECH 2.0 scale), analysis of growth factors and inflammatory cytokines (ELISA test), pain levels (VAS scale) and quality of life (CIVIQ 20).

If confirmed, BAMS-based therapy may provide an effective treatment for VLUs, potentially reducing wound closure time and associated complications. This therapy could significantly enhance patients' quality of life due to the regenerative and analgesic properties of the biological dressing.

Given the biological activity of mesenchymal stem cells, an accelerated healing effect is expected in the treatment group. This could lead to shorter healing times for chronic wounds, resulting in significant benefits for patients, healthcare professionals, and overall healthcare costs.

NCT05962931.

Premature ovarian insufficiency (POI) poses a significant threat to female reproductive health and currently lacks effective interventions. Recent studies highlight the promising potential of human pluripotent stem cell-derived mesenchymal stem cells (hPSC-MSC) in regenerative medicine. However, research on hPSC-MSC-based treatments for POI remains limited, particularly in the characterization of the intermediate differentiation stages from hPSC to MSC. This study presents an accelerated differentiation protocol for generating hPSC-MSC via neural crest cells (NCC) and evaluates their therapeutic potential in chemotherapy-induced POI.

We modified a canonical small molecule-mediated protocol for hPSC-NCC-MSC differentiation. Systematic characterization of differentiated-cells was performed using qPCR, immunofluorescence, cell viability assays, flow cytometry and trilineage differentiation. In vivo, hPSC-NCC-MSC were transplanted into chemotherapy-induced POI SD rat models, and parameters such as body weight, ovarian weight, estrous cycle, hormone levels, follicle count, and mating were assessed. Granulosa cells (GC) apoptosis was analyzed using TUNEL assay and immunohistochemistry. In vitro, their effects on apoptosis inhibition and oxidative stress alleviation were investigated in a cultured GC cell line. Additionally, comparisons between umbilical cord MSC (UC-MSC) and hPSC-NCC-MSC in chemotherapy-induced POI was conducted.

Our optimized protocol, combining CHIR99021 and SB431542, efficiently induced NCC from both human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC). The programmed hPSC-NCC-MSC, characterized by specific NCC markers (P75, HNK1, SOX10, and AP2α), exhibited typical MSC morphology, trilineage differentiation potential, favorable cell viability, and prominent anti-senescence properties. Among these, NCC differentiated from H1-hESCs (H1-NCC) demonstrated the highest induction efficiency (72.45%), and H1-NCC-derived MSC (H1-NCC-MSC) displayed superior proliferation and anti-senescence properties compared to UC-MSC. Besides, H1-NCC-MSC exhibited therapeutic efficacy comparable to UC-MSC in both in vivo and in vitro models of chemotherapy-induced POI, potentially through mechanisms involving reduced GC apoptosis, alleviated oxidative stress, and improved mitochondrial function.

Our findings propose a modified hPSC-NCC-MSC differentiation protocol, offering an inexhaustible and stable source for regenerative therapies. Furthermore, we provide the first experimental evidence that hPSC-NCC-MSC have therapeutic potential comparable to UC-MSC in restoring chemotherapy-induced POI. The underlying mechanisms are likely associated with paracrine-mediated effects on GC apoptosis, oxidative stress, and mitochondrial dysfunction.

Bone is a dynamic tissue that constantly undergoes remodeling processes throughout life to maintain its structure and integrity. During this process, physiological bone turnover, which is shaped by apoptosis, occurs in cells in the bone microenvironment. The clearance of these apoptotic cells (ACs) is executed by phagocytes through a process called efferocytosis, which simply means taking to the grave "burial." Efferocytosis is a multistage process involving the recognition, binding, internalization, and digestion of ACs, culminating in the resolution of inflammation. Critically, aberrations in efferocytosis lead to the accumulation of apoptotic corpses, impairing tissue homeostasis and contributing to various pathologies as well as bone-related diseases. Emerging evidence suggests that modulating/activating efferocytosis at any stage represents a promising therapeutic strategy for managing bone-related diseases, especially those associated with aging and inflammation. This review discusses the current understanding of the cellular and molecular mechanisms of efferocytosis, its roles within the bone microenvironment, and potential therapeutic interventions targeting efferocytosis in age-related bone diseases.

Upon inflammation, the bone marrow (BM) landscape undergoes significant architectural and functional modifications. Stimulation of the hematopoietic niche triggers a series of lightning events, which begin with stem/progenitor blood elements mobilization and culminates with the activation of immune responses. Ageing partially mirrors this process, albeit with a propensity towards chronic inflammation and immune dysfunction. Age-related chronic inflammation disrupts bone homeostasis and accompanies impaired tissue regeneration. Thus, focusing on the bone marrow's dynamics during inflammatory bone diseases could lay the way for the development of novel therapeutic platforms aimed at niche reprogramming. Herein, we summarize inflammatory and age-induced processes in multiple BM compartments, with particular reference to hematopoietic, stromal stem/progenitor cells, and mature immunocytes. Finally, we focus on autophagy and its potential to clinically re-modulate the pathological "flogistic" bias, possibly by restoring functional phenotypes within the bone marrow niche elements.

Sepsis is a life-threatening condition with cardiac complications being an independent predictor of poor outcome. Although their mechanisms have been widely investigated, therapeutic options remain limited. One promising therapeutic tool are mesenchymal stromal cells (MSCs). The aim of this study is to investigate the immunomodulatory effects of human MSCs from two different sources (bone marrow/BMMSC and adipose tissue/ASC) and to evaluate their cardioprotective potential.

60 adult male C57BL/6 mice were divided into sham, sepsis (cecal ligation puncture (CLP)) and two i.v. treatment groups CLP + human BMMSC and CLP + human ASC with 5 animals in each group. The observation periods were 8, 24 and 72 h. Left ventricular tissue was analyzed histologically, by qPCR (C3ar, C5ar1, Il-1b, Il-6, Il-10, Tlr2, Tlr4, Tnfa, and Nlrp3) and western blot. Cardiac damage markers troponin I and heart fatty acid binding protein (HFABP) were detected in serum by ELISA.

Troponin I and HFABP were significantly increased in CLP group after 8 h compared to sham. In cardiac tissue the expression of C3ar, C5ar1, Il-1b, Il-6, Il-10, Tlr2, Tlr4, Tnfa and Nlrp3 inflammasome was upregulated up to 24h after CLP compared to sham. After BMMSC treatment, C3ar as well as C5ar, Tlr2 and Il-10 mRNA expression in left ventricle was downregulated compared to CLP, whereas ASC treatment was associated with the downregulation of Il-6 and Nlrp3.

CLP-induced polymicrobial sepsis in mice was associated with cardiac damage and increased inflammation in left ventricular tissue. Therapeutic systemic application of human BMMSC and ASC ameliorated damage and inflammation in the heart.

Tissue engineering has been an integral part of regenerative medicine. Functional biomimetic structures were assembled by combining appropriate scaffolds with specific cells. The decellularization of animal tissue preserved the natural biochemical components and structural properties of the extracellular matrix (ECM) of specific organs, thereby providing a suitable niche for tissue-specific cell differentiation and growth. In this study, the extracellular matrix (ECM) of the porcine aorta was obtained through trypsin-based decellularization. The resulting porcine aortic ECM retained a favorable collagen composition, exhibited no cytotoxicity, and demonstrated chemophilic properties for mesenchymal stem cells. Human adipose-derived mesenchymal stem cells (hADSCs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiMSCs) were transplanted onto the decellularized porcine aortic ECM, where successful differentiation into a mature cartilage layer was observed. These findings suggested that the porcine aortic ECM could serve as a potential scaffold with tubular and linear structures for tissue engineering applications. Functional human iMSCs (induced-mesenchymal stem cells) were generated from human iPSCs (induced-pluripotent stem cells) and analyzed for differences compared to primary MSCs via RNA-seq. The hiMSCs were applied to decellularized porcine aortic ECM (extracellular matrix), demonstrating chondrogenic differentiation and confirming the usability of xenogeneic ECM.

While mesenchymal stem/stromal cells (MSCs) exhibit the ability to self-renew, they are not immortal; they eventually reach a point of irreversible growth cessation and functional deterioration following a limited series of population doublings, referred to as replicative senescence. When evaluated according to the criteria set by the International Society for Cell Therapy (ISCT), MSCs show significant differences in their senescence patterns and other characteristics related to their phenotype and function. These differences are attributed to the source of the MSCs and the conditions in which they are grown. MSCs derived from fetal or adult sources have variations in their genome stability, as well as in the expression and epigenetic profile of the cells, which in turn affects their secretome. Understanding the key factors of MSC senescence based on cell source can help to develop effective strategies for regulating senescence and improving the therapeutic potential.

Mesenchymal stem cells (MSCs) are multipotent progenitors capable of self-renewal and differentiation into various cell lineages, making them essential for tissue repair and regenerative medicine. However, their regenerative potential is constrained by replicative senescence, an irreversible growth arrest that occurs after a finite number of cell divisions. In this study, we serially passaged human bone marrow-derived MSCs (bMSCs) and compared young, pre-senescent, and senescent cells. The onset of senescence was accompanied by progressive alterations in mitochondrial dynamics, leading to a decline in mitochondrial membrane potential, and increased reactive oxygen species (ROS) production, alongside a diminished cellular antioxidant capacity. These mitochondrial defects play a role in metabolic reprogramming in senescent bMSCs. Our findings underscore the intricate interplay between ROS, mitochondrial dysfunction, and replicative senescence, offering valuable insights to guide the development of therapeutic strategies for preserving MSC functionality in aging and MSC-based therapies.

Mesenchymal stem cells (MSCs) have several important properties that make them desirable for regenerative medicine. These properties include immunomodulatory ability, growth factor production, and differentiation into various cell types. Despite extensive research and promising results in clinical trials, our understanding of MSC biology, their mechanism of action, and their targeted and routine use in clinics is limited. Differentiation of human MSCs (hMSCs) is a complex process influenced by various elements such as growth factors, pharmaceutical compounds, microRNAs, 3D scaffolds, and mechanical and electrical stimulation. Research has shown that different culture conditions can affect the differentiation potential of hMSCs obtained from multiple fetal and adult sources. Additionally, it seems that what affects the differentiation capacities of these cells is their secretory characteristics, which are influenced by the origin of the cells and the local microenvironment where the cells are located. The review can provide insights into the microenvironment-based mechanisms involved in MSC differentiation, which can be valuable for future therapeutic applications.

Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration.

Exosomes (Exos) are extracellular vesicles secreted by cells and serve as crucial mediators of intercellular communication. They play a pivotal role in the pathogenesis and progression of various diseases and offer promising avenues for therapeutic interventions. Exos derived from mesenchymal stem cells (MSCs) have significant immunomodulatory properties. They effectively regulate immune responses by modulating both innate and adaptive immunity. These Exos can inhibit excessive inflammatory responses and promote tissue repair. Moreover, they participate in antigen presentation, which is essential for activating immune responses. The cargo of these Exos, including ligands, proteins, and microRNAs, can suppress T cell activity or enhance the population of immunosuppressive cells to dampen the immune response. By inhibiting lymphocyte proliferation, acting on macrophages, and increasing the population of regulatory T cells, these Exos contribute to maintaining immune and metabolic homeostasis. Furthermore, they can activate immune-related signaling pathways or serve as vehicles to deliver microRNAs and other bioactive substances to target tumor cells, which holds potential for immunotherapy applications. Given the immense therapeutic potential of MSC-derived Exos, this review comprehensively explores their mechanisms of immune regulation and therapeutic applications in areas such as infection control, tumor suppression, and autoimmune disease management. This article aims to provide valuable insights into the mechanisms behind the actions of MSC-derived Exos, offering theoretical references for their future clinical utilization as cell-free drug preparations.

Publications of Soufan et al and Kristjánsson et al in the World Journal of Orthopedics on mesenchymal stem cell (MSC) therapy for osteoarthritis (OA) represent a significant exploration of regenerative medicine's potential in OA treatment. In their research, it is highlighted that MSCs can alleviate OA symptoms and even regenerate cartilage, potentially reversing the disease. They also compared the efficacy of three MSC subtypes, emphasizing the therapeutic advantages of adipose-derived MSCs. MSC injections, a novel and less invasive alternative to traditional treatments such as chondrocyte transplantation or arthroplasty, have a low cost, low risks, and favorable outcomes, presenting a promising approach for OA patients. Additionally, we stressed that the efficacy evaluation criteria, heterogeneity, safety, and other factors must be carefully considered to further advance the clinical translation of MSC therapy for OA.

Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies, despite uncertainty about its clinical therapeutic efficacy and unclear underlying mechanisms. Here, we investigated the role of follistatin-like 1 (FSTL1), a profibrotic and proinflammatory matricellular protein, in inflammation-related heterogeneity in stem cell therapy. Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis. FSTL1 facilitated MSC-mediated early recruitment of Ly6C+ inflammatory macrophages within 24 h postinfusion, which was essential for the empowerment of MSCs and subsequent Ly6C-CX3CR1+ macrophage remodelling at 48 h postinfusion. Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C-CX3CR1+ macrophage accumulation, resulting in the poor antifibrotic effect of MSCs in mice. Whereas, recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl4-injured Fstl1+/- mice. Mechanistically, host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NF-κB/ATP6V1G2 axis, leading to early recruitment of Ly6C+ monocytes /macrophages. Taken together, our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy. These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.

Cardiovascular diseases are a leading cause of morbidity and mortality in dogs, with limited options available for reversing myocardial damage. Stem cell therapies have shown significant potential for cardiac repair, owing to their immunomodulatory, antifibrotic, and regenerative properties. This review evaluates the therapeutic applications of mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue, and Wharton's jelly with a focus on their role in canine cardiology and their immunoregulatory properties. Preclinical studies have highlighted their efficacy in enhancing cardiac function, reducing fibrosis, and promoting angiogenesis. Various delivery methods, including intracoronary and intramyocardial injections, are assessed for their safety and efficacy. Challenges such as low cell retention, differentiation efficiency, and variability in therapeutic responses are also discussed. Emerging strategies, including genetic modifications and combination therapies, aim to enhance the efficacy of MSCs. Additionally, advances in delivery systems and regulatory frameworks are reviewed to support clinical translation. This comprehensive evaluation underscores the potential of stem cell therapies to revolutionize canine cardiovascular disease management while identifying critical areas for future research and clinical integration.

Excessively activated M1 microglia release proinflammatory factors that can cause neuronal death and contribute to the development of Parkinson's disease (PD). Recent research indicates that spermidine, a naturally occurring polyamine, may have anti-inflammatory properties. Nonetheless, the specific role of spermidine in Parkinson's disease, particularly how it affects microglia-driven neuroinflammation and the balance between M1 and M2 polarization, is still not fully understood.

We examined the effects of spermidine on the polarization of M1/M2 microglia in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and lipopolysaccharide (LPS)-stimulated BV2 cells. Methods like RT-PCR, western blotting, and immunofluorescence were used to examine how spermidine influences the polarization of microglia.

In vivo, spermidine pretreatment reduced the activation of M1 microglia and encouraged the transformation of microglia into the M2 phenotype in the substantia nigra (SN) of PD mice. Additionally, spermidine decreased the release of inflammatory factors and lessened the death of dopaminergic neurons in the SN of these mice. In vitro, spermidine indirectly protected neurons from death by affecting microglial polarization. Furthermore, spermidine preconditioning led to decreased phosphorylation of NF-κB, STAT1, and p38 MAPK, while enhancing the phosphorylation of STAT6, both in vivo and in vitro. Additionally, we observed that the supernatant from BV2 cells was cultured with SH-SY5Y neurons. The findings revealed that the supernatant from LPS-activated BV2 cells notably reduced the viability of SH-SY5Y cells, as well as the levels of brain-derived neurotrophic factor (BDNF), TrkB, PI3K, and p-AKT. However, these effects were significantly reversed by pretreatment with spermidine.

Our research found that spermidine reduced M1 microglial polarization, partially through the inhibition of the NF-κB, STAT1, and p38 MAPK pathways, and encouraged M2 microglial polarization by activating the STAT6 pathway. This action helped to mitigate neuroinflammation in both the MPTP mouse model of Parkinson's disease and LPS-stimulated BV2 cells. Additionally, spermidine provided indirect neuroprotection by activating BDNF-TrkB-PI3K/AKT signaling pathways.

Mesenchymal stem cells (MSCs) are a source of a wide range of soluble factors, including different proteins, growth factors, cytokines, chemokines, and DNA and RNA molecules, in addition to numerous secondary metabolites and byproducts of their metabolism. MSC secretome can be formally divided into secretory and vesicular parts, both of which are very important for intercellular communication and are involved in processes such as angiogenesis, proliferation, and immunomodulation. Exosomes are thought to have the same content and function as the MSCs from which they are derived, but they also have a number of advantages over stem cells, including low immunogenicity, unaltered functional activity during freezing and thawing, and a lack of tumor formation. In addition, MSC pre-treatment with various inflammatory factors or hypoxia can alter their secretomes so that it can be modified into a more effective treatment. Paracrine factors secreted by MSCs improve the survival of other cell populations by several mechanisms, including immunomodulatory (mostly anti-inflammatory) activity and anti-apoptotic activity partly based on Hsp27 upregulation. Reproductive medicine is one of the fields in which this cell-free approach has been extensively researched. This review presents the possible applications and challenges of using MSC secretome in the treatment of infertility. MSCs and their secretions have been shown to have beneficial effects in various models of female and male infertility resulting from toxic damage, endocrine disorders, trauma, infectious agents, and autoimmune origin.

Articular cartilage (AC) is a specialized connective tissue with unique biological and mechanical properties, which depends on the biological effects of each resident chondrocyte and its surrounding extracellular matrix (ECM) to form a unit that operates in a constant and balanced feedback loop. The surface membrane receptors of chondrocytes play a crucial role in the feedback balance of this biological unit. Various biological signals outside chondrocytes, such as water-soluble chemical signal molecules and mechanical signals, are unable to directly enter the cell and must first bind to the plasma membrane receptors to induce changes in the level and activity of intracellular signal transduction molecules. These changes then transmit through signaling cascade pathways into the nucleus, changing the cell phenotype, and producing physiological or pathological changes. Specific chemical and mechanical signals break the feedback balance of cartilage tissue units through membrane receptors. In the ECM environment, the molecular actions of chondrocyte membrane receptors in response to these specific signals, along with associated ion channel receptors, collectively regulate the biological effects of chondrocytes. This leads to decreased chondrocyte survival and an imbalance in ECM regulation, ultimately disrupting the tissue's molecular framework and physiological feedback mechanisms, and resulting in pathological changes in cartilage tissue. To provide insights into addressing the complexities associated with cartilage tissue injury and repair engineering, this review provides a comprehensive overview of the molecular mechanisms and biological implications of chondrocyte membrane receptor-mediated signal transduction, including G protein-coupled receptors (GPCRs), enzyme-linked receptors (tyrosine kinase receptors (TKRs)), and integrin receptors.

Traumatic brain injury (TBI) is a complex condition involving mechanisms that lead to brain dysfunction and nerve damage, resulting in significant morbidity and mortality globally. Affecting ~50 million people annually, TBI's impact includes a high death rate, exceeding that of heart disease and cancer. Complications arising from TBI encompass concussion, cerebral hemorrhage, tumors, encephalitis, delayed apoptosis, and necrosis. Current treatment methods, such as pharmacotherapy with dihydropyridines, high-pressure oxygen therapy, behavioral therapy, and non-invasive brain stimulation, have shown limited efficacy. A comprehensive understanding of vascular components is essential for developing new treatments to improve blood vessel-related brain damage. Recently, mesenchymal stem cells (MSCs) have shown promising results in repairing and mitigating brain damage. Studies indicate that MSCs can promote neurogenesis and angiogenesis through various mechanisms, including releasing bioactive molecules and extracellular vesicles (EVs), which help reduce neuroinflammation. In research, the distinctive characteristics of MSCs have positioned them as highly desirable cell sources. Extensive investigations have been conducted on the regulatory properties of MSCs and their manipulation, tagging, and transportation techniques for brain-related applications. This review explores the progress and prospects of MSC therapy in TBI, focusing on mechanisms of action, therapeutic benefits, and the challenges and potential limitations of using MSCs in treating neurological disorders.

Drug delivery to cancer cells continues to present a major therapeutic challenge. Mesenchymal stem cells (MSCs) possess an intrinsic ability to migrate specifically to tumor tissues, making them promising candidates for targeted drug delivery. Evidence from preclinical studies indicates that MSCs loaded with therapeutic anti-cancer agents exhibit considerable anti-tumor activity. Moreover, several clinical trials are currently evaluating their effectiveness in cancer patients. The integration of MSCs with synthetic nanoparticles (NPs) enhances their therapeutic potential, particularly through the use of cell membrane-coated NPs, which represent a significant advancement in the field. This review systematically investigates the tumor microenvironment, the sources of MSCs, the tumor homing mechanisms, and the methods of loading and releasing anticancer drugs from MSCs. Furthermore, cutting-edge strategies to improve the efficacy of MSCs based drug delivery systems (DDS) including the innovative use of MSC membrane coated nanoparticles have been discussed. The study concludes with an overview of the therapeutic use of MSCs as drug carriers, including a detailed analysis of the mechanisms by which MSCs deliver therapeutics to cancer cells, enabling targeted drug delivery. It aims to elucidate the current state of this approach, identify key areas for development, and outline potential future directions for advancing MSCs based cancer therapies.

Stem cells are undifferentiated or partially differentiated cells with an extraordinary ability to self-renew and differentiate into various cell types during growth and development. The epithelial-mesenchymal transition (EMT), a critical developmental process, enhances stem cell-like properties in cells, and is associated with both normal stem cell function and the formation of cancer stem cells. Cell stemness and the EMT often coexist and are interconnected in various contexts. Cancer stem cells are a critical tumor cell population that drives tumorigenesis, cancer progression, drug resistance, and metastasis. Stem cell differentiation and the generation of cancer stem cells are regulated by numerous molecules, including microRNAs (miRNAs). These miRNAs, particularly through the modulation of EMT-associated factors, play major roles in controlling the stemness of cancer stem cells. This review presents an up-to-date summary of the regulatory roles of miR-181 in human stem cell differentiation and cancer cell stemness. We outline studies from the current literature and summarize the miR-181-controlled signaling pathways responsible for driving human stem cell differentiation or the emergence of cancer stem cells. Given its critical role in regulating cell stemness, miR-181 is a promising target for influencing human cell fate. Modulation of miR-181 expression has been found to be altered in cancer stem cells' biological behaviors and to significantly improve cancer treatment outcomes. Additionally, we discuss challenges in miRNA-based therapies and targeted delivery with nanotechnology-based systems.

Aging is an intricate and gradual process characterized by tissue and cellular dysfunction. Adipose-derived mesenchymal stem cells (ADMSCs) experience a functional decline as part of systemic aging. However, the alterations in ADMSCs across various anatomical sites throughout an individual's lifespan remain unclear. To shed light on these changes, we collected white adipose tissue and brown adipose tissue samples from the epididymis, perirenal, inguinal, and scapular regions of young, adult, and aged rats and subsequently isolated ADMSCs for RNA sequencing. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Marker genes of ADMSCs from different sites were identified. Aging triggered notable activation of inflammatory and immune responses while diminishing the ADMSC differentiation capacity and ability to maintain a normal tissue morphology. Furthermore, miR-195-5p and miR-497-3p, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation, were positively correlated with aging. These findings increase our understanding of ADMSC senescence and underscore the unique physiological changes and functions of ADMSCs across different anatomical sites during aging.NEW & NOTEWORTHY Dynamic changes in mRNAs and miRNAs of ADMSCs during aging are shown. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Aging leads to the activation of inflammatory and cellular dysfunction. miR-195-5p and miR-497-3p are positively correlated with aging, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation. ADMSCs associated with different anatomical sites have site-specific markers.

Every 25th death worldwide is associated with liver pathology. The development of novel approaches to liver diseases therapy and protocols for maintaining the vital functions of patients on the liver transplant waiting list are urgently needed. Resident mesenchymal stem cells (MSCs) play a significant role in supporting liver tissue integrity and improve the liver condition after infusion. However, it remains unclear whether MSCs isolated from chronically inflamed livers are similar in their basic cellular properties to MSCs obtained from healthy livers. We applied a large array of tests to compare resident MSCs isolated from apparently normal liver tissue and from chronically inflamed livers of patients with fibrosis, cirrhosis, and viral hepatitis. Chronic inflammatory environment did not alter the major cellular characteristics of MSCs, including the expression of MSC markers, stem cell markers, adhesion molecules, and the hallmarks of senescence, as well as cell proliferation, migration, and secretome. Only the expression of some immune checkpoints and toll-like receptors was different. Evidently, MSCs with unchanged cellular properties are present in human liver even at late stages of inflammatory diseases. These cells can be isolated and used as starting material in the development of cell therapies of liver diseases.

Ischemic stroke (IS) is a disease with high mortality and disability rates worldwide and is a serious threat to patient health. Owing to the narrow therapeutic window, effective treatments during the recovery period are limited. However, in recent years, mesenchymal stem cells (MSCs) have attracted attention and have shown therapeutic potential in IS treatment because of their abilities to home and secrete multiple bioactive substances and potential for differentiation and substitution. The therapeutic mechanisms of MSCs in IS include the regulatory effects of MSCs on microglia, the dual role of MSCs in astrocytes, how MSCs connect innate and adaptive immunity, the secretion of cytokines by MSCs to counteract apoptosis and MSC apoptosis, the promotion of angiogenesis by MSCs to favor the restoration of the blood‒brain barrier (BBB), and the potential function of local neural replacement by MSCs. However, the low graft survival rate, insufficient homing, poor targeting, and inability to achieve directional differentiation of MSCs limit their wide application. As an approach to compensate for the shortcomings of MSCs, scientists have used nanomaterials to assist MSCs in homing, survival and proliferation. In addition, the unique material of nanomaterials adds tracking, imaging and real-time monitoring to stroke treatment. The identification of effective treatments for stroke is urgently needed; thus, an understanding of how MSCs treat stroke and further improvements in the use of nanomaterials are necessary.

The study of fetal gut development is critical due to its substantial influence on immediate neonatal and long-term adult health. Current research largely focuses on microbiome colonization, gut immunity, and barrier function, alongside the impact of external factors on these phenomena. Limited research has been dedicated to the categorization of developing fetal gut cells. Our study aimed to enhance our understanding of fetal gut development by employing advanced machine-learning techniques on single-cell sequencing data. This dataset consisted of 62,849 samples, each characterized by 33,694 distinct gene features. Four feature ranking algorithms were utilized to sort features according to their significance, resulting in four feature lists. Then, these lists were fed into an incremental feature selection method to extract essential genes, classification rules, and build efficient classifiers. Several important genes were recognized by multiple feature ranking algorithms, such as FGG, MDK, RBP1, RBP2, IGFBP7, and SPON2. These features were key in differentiating specific developing intestinal cells, including epithelial, immune, mesenchymal, and vasculature cells of the colon, duo jejunum, and ileum cells. The classification rules showed special gene expression patterns on some intestinal cell types and the efficient classifiers can be useful tools for identifying intestinal cells.

Bone marrow-mesenchymal stromal cells (BM-MSCs) are key components of the BM niche, where they regulate hematopoietic stem progenitor cell (HSPC) homeostasis by direct contact and secreting soluble factors. BM-MSCs also protect the BM niche from excessive inflammation by releasing anti-inflammatory factors and modulating immune cell activity. Thanks to these properties, BM-MSCs were successfully employed in pre-clinical HSPC transplantation models, increasing the rate of HSPC engraftment, accelerating the hematological reconstitution, and reducing the risk of graft failure. However, their clinical use requires extensive in vitro expansion, potentially altering their biological and functional properties. In this work, we analyzed the transcriptomic profile of human BM-MSCs sorted as CD45-, CD105+, CD73+, and CD90+ cells from the BM aspirates of heathy-donors and corresponding ex-vivo expanded BM-MSCs. We found the expression of immune and inflammatory genes downregulated upon cell culture and selected the transcription factor EGR1 to restore the MSC properties. We overexpressed EGR1 in BM-MSCs and performed in vitro tests to study the functional properties of EGR1-overexpressing BM-MSCs. We concluded that EGR1 increased the MSC response to inflammatory stimuli and immune cell control and potentiated the MSC hematopoietic supportive activity in co-culture assay, suggesting that the EGR1-based reprogramming may improve the BM-MSC clinical use.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by axial osteoarticular inflammation and tendon enthesitis with unclear pathogenesis. Nonsteroidal anti-inflammatory drugs and antirheumatic drugs used in the traditional treatment of AS have some problems such as drug intolerance and inadequate treatment response. Since the introduction of biological agents in the treatment of AS, they have completely changed the treatment concept of AS, and because of their safety and good tolerance, they have become the main choice for clinical AS patients. This article systematically summarizes the current status of targeted therapy for AS worldwide, analyzes the advantages and disadvantages of different types of biological agents in the treatment of AS, and provides an objective evaluation of clinical targeted therapy for AS, in order to provide a new perspective for clinical standardized treatment.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, and inflammatory signaling is involved in its pathogenesis. Cytokines exert a robust effect on the progression of AML and affect survival outcomes. The dysregulation in the cytokine network may foster a pro-tumorigenic microenvironment, increasing leukemic cell proliferation, decreasing survival and driving drug resistance. The dominance of pro-inflammatory mediators such as IL-11β, TNF-α and IL-6 over anti-inflammatory mediators such as TGF-β and IL-10 has been implicated in tumor progression. Additionally, inflammatory cytokines have favored certain populations of hematopoietic stem and progenitor cells with mutated clonal hematopoiesis genes. This article summarizes current knowledge about inflammatory cytokines and signaling pathways in AML, their modes of action and the implications for immune tolerance and clonal hematopoiesis, with the aim of finding potential therapeutic interventions to improve clinical outcomes in AML patients.

Progressive heart failure with reduced ejection fraction (HFrEF) is adversely affected by alterations in the myocardial balance between bone marrow-derived pro-inflammatory cardiac macrophages and embryo-derived reparative cardiac resident macrophages. Mesenchymal precursor cells (MPCs) may restore this balance and improve clinical outcomes when inflammation is present. The purpose was to (i) identify risk factors for cardiovascular death (CVD) in control patients with HFrEF in the DREAM-HF trial, and (ii) determine if MPCs improve major clinical outcomes (CVD, myocardial infarction [MI], stroke) in high-risk patients with ischaemic HFrEF and inflammation.

Cause-specific regression analyses were used to identify CVD risk factors in DREAM-HF control patients. Aalen-Johansen cumulative incidence curves were used to examine CVD, 2-point major adverse cardiovascular events (MACE) (MI or stroke), and 3-point MACE (CVD or MI or stroke) by treatment group in ischaemic vs non-ischaemic HFrEF and in patients with or without baseline inflammation. In control DREAM-HF patients, factors portending the greatest risk for CVD were inflammation (baseline plasma high-sensitivity C-reactive protein ≥2 mg/L; p = 0.003) and ischaemic HFrEF aetiology (p = 0.097), with increased CVD risk of 61% and 38%, respectively. Over 30-month mean follow-up, MPCs reduced 2-point and 3-point MACE by 88% (p = 0.005) and 52% (p = 0.018), respectively, in patients with ischaemic HFrEF and inflammation compared to controls.

Ischaemic aetiology and inflammation were identified as major risk factors for MACE in control DREAM-HF patients. A single intramyocardial MPC administration produced the most significant, sustained reduction in 2-point and 3-point MACE in patients with ischaemic HFrEF and inflammation.

Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. In addition to the wear and tear of joints, aberrant remodelling driven by a significant presence of inflammatory mediators within the joint is one of the key mechanisms in the pathogenesis of OA. Among these factors, hyperactivation of Teffs subsets plays a crucial role in promoting this pathological process. The immune imbalance between proinflammatory CD4+ effector T cells (proinflammatory Teffs) and Tregs could be a crucial factor in the pathogenesis of OA. Therefore, correcting the imbalance of Tregs/proinflammatory Teffs may slow or inhibit the occurrence and development of OA, which could be a potential target for the treatment of OA. Mesenchymal stem cells (MSCs) possess anti-inflammatory and immunomodulatory properties, regulating both adaptive and innate immunity through mechanisms involving soluble factors such as IDO, PGE2, and TGF-β, as well as cell-to-cell contact and exosomes. Correcting the imbalance between Tregs and proinflammatory Teffs may be one of the mechanisms of MSCs in the treatment of OA. Therefore, this review aims to summarize the relationship between OA and the immune imbalance between Tregs and proinflammatory Teffs, the immunoregulatory role of Tregs in OA, and the role of MSCs and their exosomes in correcting the imbalance between Tregs and proinflammatory Teffs.

Stem cell-based therapy has gained importance over the past decades due to huge advances in science and technology behind the generation and directed differentiation of pluripotent cells from embryos and adult cells. Preclinical proof-of-concept studies have been followed by clinical trials showing efficacy and safety of transplantation of stem cell-based therapy, which are beginning to establish this as a modality of treatment. Disease candidates of interest are primarily conditions that may benefit from replacing dead or dying cells, including advanced inherited retinal dystrophies and age-related macular degeneration, and predominantly seek to transplant either RPE or photoreceptors, although neurotrophic approaches have also been trialed. Whilst a consensus has yet to be reached about the best stage/type of cells for transplantation (stem cells, progenitor cells, differentiated RPE and photoreceptors) and the methods of implantation (sheet, suspension), several CTs have shown safety. There remain potential concerns regarding tumorigenicity and immune rejection; however, with ongoing improvements in cell generation, selection, and delivery, these can be minimized. Earlier studies showed efficacy with immunosuppressive drugs to prevent rejection, and recent donor-matched transplants have avoided the need for immunosuppression. Retinal regenerative medicine is a challenging field and is in a nascent stage but holds tremendous promise. This narrative review delves into the current understanding of stem cells and the latest clinical trials of retinal cell transplantation.

Breast implant surgery has evolved significantly, yet challenges such as capsular contracture remain a persistent concern. This review presents an in-depth analysis of recent advancements in understanding the immune mechanisms and clinical implications associated with silicone mammary implants (SMIs). The article systematically examines the complex interplay between immune responses and capsular fibrosis, emphasizing the pathophysiological mechanisms of inflammation in the etiology of this fibrotic response. It discusses innovations in biomaterial science, including the development of novel anti-biofilm coatings and immunomodulatory surfaces designed to enhance implant integration and minimize complications. Emphasis is placed on personalized risk assessment strategies, leveraging molecular insights to tailor interventions and improve patient outcomes. Emerging therapeutic targets, advancements in surgical techniques, and the refinement of post-operative care are also explored. Despite notable progress, challenges such as the variability in immune responses, the long-term efficacy of new interventions, and ethical considerations remain. Future research directions are identified, focusing on personalized medicine, advanced biomaterials, and bridging preclinical findings with clinical applications. As we advance from bench to bedside, this review illuminates the path forward, where interdisciplinary collaboration and continued inquiry weave together to enhance the art and science of breast implant surgery, transforming patient care into a realm of precision and excellence.

As an immune-related tumor type, bladder cancer has been attracting much attention in the study of its markers. In recent years, researchers have made rapid progress in the study of immune-related markers for bladder cancer. Studies have shown that immune-related markers play an important role in the diagnosis, prognosis assessment and treatment of bladder cancer. In addition, the detection of immune-related markers can also be used to evaluate the efficacy of immunotherapy and predict the treatment response of patients. Therefore, in depth study of the expression of immune-related markers in bladder cancer and their application in the clinic is of great significance and is expected to provide new breakthroughs for individualized treatment of bladder cancer. Future studies will focus more on how to detect immune-related markers with low cost and high accuracy, as well as develop new immunotherapeutic strategies to bring better therapeutic outcomes to bladder cancer patients.

Mesenchymal stromal cells (MSCs) exhibit significant potential in the context of cell therapy because of their capacity to perform a range of interconnected functions in damaged tissues, including immune modulation, hematopoietic support, and tissue regeneration. MSCs are hypoimmunogenic because of their diminished expression of major histocompatibility molecules, absence of costimulatory molecules, and presence of coinhibitory molecules. While autologous MSCs reduce the risk of rejection and infection, variability in cell numbers and proliferation limits their potential applications. Conversely, allogeneic MSCs (allo-MSCs) possess broad clinical applications unconstrained by donor physiology. Nonetheless, preclinical and clinical investigations highlight that transplanted allo-MSCs are subject to immune attack from recipients. These cells exhibit anti-inflammatory and proinflammatory phenotypes contingent on the microenvironment. Notably, the proinflammatory phenotype features enhanced immunogenicity and diminished immunosuppression, potentially triggering allogeneic immune reactions that impede long-term clinical efficacy. Consequently, preserving the low immunogenicity of allo-MSCs in vivo and mitigating immune rejection in diverse microenvironments represent crucial challenges for the widespread clinical application of MSCs. In this review, we elucidate the immune regulation of allo-MSCs, specifically focusing on two distinct subgroups, MSC1 and MSC2, that exhibit varying polarization states and immunogenicity. We discuss the factors and underlying mechanisms that induce MSC immunogenicity and polarization, highlighting the crucial role of major histocompatibility complex class I/II molecules in rejection post-transplantation. Additionally, we summarize the immunogenic regulatory targets and applications of allo-MSCs and outline strategies to address challenges in this promising field, aiming to enhance allo-MSC therapeutic efficacy for patients.

The present study was aimed to explore the possible mechanisms by which caprine Wharton's jelly-derived MSCs (WJ-MSCs) perform their immunomodulatory function. WJ-MSCs were isolated through explants culture and characterized as per ISCT criteria using culture behavior, expression of surface markers by PCR, FACS and immunocytochemical localization (ICC), trilineage differentiation potential etc. Secretory behavior for important biomolecules (IDO, TGFβ1, VEGF, IL6) was evaluated by ICC and western blot assay. Cell-to-cell communication was studied by culturing cells in cell-cell contact and trans-well system. The MSCs when co-cultured with activated Tc and Th cells, down-regulation of T cell cytokine as well as upregulation of immunomodulatory factors (VEGF A, IL10, IL6, IDO, iNOS, PTGS2, HGF, TGFβ, CXCL10, CXCL11) was noticed in both cell-cell contact and trans-well culture system which was significantly higher in cell-cell contact system. Trilineage differentiation of MSCs showed significant upregulation of MHC I (CAHI) and MHC II (CLA DRB3) molecules suggesting better clinical applications of MSCs without differentiation to avoid immune rejection. It can be concluded that WJ-MSCs perform their immunomodulation through the secretion of a battery of biomolecules and work in both cell-cell contact manner and through their secretome.