Excess glucose alone depress young mesenchymal stromal/stem cell osteogenesis and mitochondria activity within hours/days via NAD+/SIRT1 axis.

BACKGROUND: The impact of global overconsumption of simple sugars on bone health, which peaks in adolescence/early adulthood and correlates with osteoporosis (OP) and fracture risk decades, is unclear. Mesenchymal stromal/stem cells (MSCs) are the progenitors of osteoblasts/bone-forming cells, and known to decrease their osteogenic differentiation capacity with age. Alarmingly, while there is correlative evidence that adolescents consuming greatest amounts of simple sugars have the lowest bone mass, there is no mechanistic understanding on the causality of this correlation. METHODS: Bioinformatics analyses for energetics pathways involved during MSC differentiation using human cell information was performed. In vitro dissection of normal versus high glucose (HG) conditions on osteo-/adipo-lineage commitment and mitochondrial function was assessed using multi-sources of non-senescent human and murine MSCs; for in vivo validation, young mice was fed normal or HG-added water with subsequent analyses of bone marrow CD45- MSCs. RESULTS: Bioinformatics analyses revealed mitochondrial and glucose-related metabolic pathways as integral to MSC osteo-/adipo-lineage commitment. Functionally, in vitro HG alone without differentiation induction decreased both MSC mitochondrial activity and osteogenesis while enhancing adipogenesis by 8 h' time due to depletion of nicotinamide adenine dinucleotide (NAD+), a vital mitochondrial co-enzyme and co-factor to Sirtuin (SIRT) 1, a longevity gene also involved in osteogenesis. In vivo, HG intake in young mice depleted MSC NAD+, with oral NAD+ precursor supplementation rapidly reversing both mitochondrial decline and osteo-/adipo-commitment in a SIRT1-dependent fashion within 1 ~ 5 days. CONCLUSIONS: We found a surprisingly rapid impact of excessive glucose, a single dietary factor, on MSC SIRT1 function and osteogenesis in youthful settings, and the crucial role of NAD+-a single molecule-on both MSC mitochondrial function and lineage commitment. These findings have strong implications on future global OP and disability risks in light of current worldwide overconsumption of simple sugars.

Clinical implications of hepatitis B virus core antigen-mediated immunopathologic T cell responses in chronic hepatitis B.

Hepatitis B virus (HBV) infection significantly impacts Asian populations. The influences of continuous HBV antigen and inflammatory stimulation to T cells in chronic hepatitis B (CHB) remain unclear. In this study, we first conducted bioinformatics analysis to assess T-cell signaling pathways in CHB patients. In a Taiwanese cohort, we examined the phenotypic features of HBVcore -specific T cells and their correlation with clinical parameters. We used core protein overlapping peptides from the Taiwan prevalent genotype B HBV to investigate the antiviral response and the functional implication of HBV-specific T cells. In line with Taiwanese dominant HLA-alleles, we also evaluated ex vivo HBVcore -specific T cells by pMHC-tetramers targeting epitopes within HBV core protein. Compared to healthy subjects, we disclosed CD8 T cells from CHB patients had higher activation marker CD38 levels but showed an upregulation in the inhibitory receptor PD-1. Our parallel study showed HBV-specific CD8 T cells were more activated with greater PD-1 expression than CMV-specific subset and bulk CD8 T cells. Moreover, our longitudinal study demonstrated a correlation between the PD-1 fluctuation pattern of HBVcore -specific CD8 T cells and liver inflammation in CHB patients. Our research reveals the HBV core antigen-mediated immunopathologic profile of CD8 T cells in chronic HBV infection. Our findings suggest the PD-1 levels of HBVcore -specific CD8 T cells can be used as a valuable indicator of personal immune response for clinical application in hepatitis management.

Mesenchymal Stromal/Stem Cells Know Best: The Remarkable Complexities of Its Interactions With Polymorphonuclear Neutrophils.

Polymorphonuclear neutrophils (PMNs), the predominant immune cell type in humans, have long been known as first-line effector cells against bacterial infections mainly through phagocytosis and production of reactive oxygen species (ROS). However, recent research has unveiled novel and pivotal roles of these abundant but short-lived granulocytes in health and disease. Human mesenchymal stromal/stem cells (MSCs), renowned for their regenerative properties and modulation of T lymphocytes from effector to regulatory phenotypes, exhibit complex and context-dependent interactions with PMNs. Regardless of species or source, MSCs strongly abrogate PMN apoptosis, a critical determinant of PMN function, except if PMNs are highly stimulated. MSCs also have the capacity to fine-tune PMN activation, particularly in terms of CD11b expression and phagocytosis. Moreover, MSCs can modulate numerous other PMN functions, spanning migration, ROS production, and neutrophil extracellular trap (NET) formation/NETosis, but directionality is remarkably dependent on the underlying context: in normal nondiseased conditions, MSCs enhance PMN migration and ROS production, whereas in inflammatory conditions, MSCs reduce both these functions and NETosis. Furthermore, the state of the MSCs themselves, whether isolated from diseased or healthy donors, and the specific secreted products and molecules, can impact interactions with PMNs; while healthy MSCs prevent PMN infiltration and NETosis, MSCs isolated from patients with cancer promote these functions. This comprehensive analysis highlights the intricate interplay between PMNs and MSCs and its profound relevance in healthy and pathological conditions, shedding light on how to best strategize the use of MSCs in the expanding list of diseases with PMN involvement.

Targeting Conserved Pathways in 3D Spheroid Formation of Diverse Cell Types for Translational Application: Enhanced Functional and Antioxidant Capacity.

Three-dimensional (3D) in vitro spheroid/organoid culture increasingly appears to better mimic physiological states than standard 2D systems. The biological consequence of 3D spheroids, however, differs for different cell types: for pluripotent embryonic stem cells (ESCs), differentiation and loss of stemness occur, while the converse is true for somatic and cancer cells. Despite such diverse consequences, there are likely conserved mechanisms governing 3D spheroid formation across cell types that are unknown but could be efficiently targeted for translational application. To elucidate such processes, we performed transcriptome analysis with functional validation on 2D- and 3D-cultured mouse ESCs, mesenchymal stromal/stem cells (MSCs), and cancer cells. At both the transcriptomic and functional levels, 3D spheroid formation resulted in commitment towards known cell-specific functional outcomes. Surprisingly in all cell types, downregulation of the cholesterol synthesis pathway was found during 3D spheroid formation, with modulation concomitantly affecting 3D spheroid formation and cell-specific consequences; similar results were seen with human cell types. Furthermore, improved antioxidant capacity after 3D spheroid formation across cell types was further enhanced with modulation of the pathway. These findings demonstrate the profound cell-specific consequences and the translational value of understanding conserved mechanisms across diverse cell types after 3D spheroid formation.

Migraine and subsequent head and neck cancer: A nationwide population-based cohort study.

OBJECTIVES: The association of migraine with the risk of certain cancer has been reported. The aim of this pilot study was to examine the associations between migraine and the onset of head and neck cancers (HNC). MATERIALS AND METHODS: A total of 1755 individuals were identified through a nationwide population-based cohort registry in Taiwan between 2000 and 2013. The primary end point variable was new-onset head and neck cancers in patients with migraine versus non-migraine controls. Cox proportional hazard regression was used to derive the risk of HNC. Subgroup analyses were performed to determine subpopulations at risk of migraine-associated HNC. Sub-outcome analyses were carried out to provide the subtypes of migraine-associated HNC. Propensity score matching was utilized to validate the findings. RESULTS: A total of four patients out of 351 patients with migraine and seven out of 1404 non-migraine controls developed HNC. The incidence of HNC was higher in patients with migraine than that in non-migraine controls (108.93 vs. 48.77 per 100,000 person-years) (adjusted hazard ratio, aHR = 2.908, 95% CI = 0.808-10.469; p = 0.102). The risk of HNC in patients with migraine with aura (aHR = 5.454, 95% CI = 0.948-26.875; p = 0.264) and without aura (aHR = 2.777, 95% CI = 0.755-8.473; p = 0.118) was revealed. The incidence of non-nasopharyngeal HNC secondary to migraine (112.79 per 100,000 person-years) was higher than that of nasopharyngeal cancer secondary to migraine (105.33 per 100,000 person-years). CONCLUSION: A higher incidence of HNC was observed in a small sample of patients with migraine, especially in those with migraine with aura. Migraine-associated HNC included non-nasopharyngeal HNC. Studies with a larger sample are needed to confirm the finding of the high risk of HNC in people with migraine.

Three-Dimensional Spheroid Culture of Human Mesenchymal Stem Cells: Offering Therapeutic Advantages and In Vitro Glimpses of the In Vivo State.

As invaluable as the standard 2-dimensional (2D) monolayer in vitro cell culture system has been, there is increasing evidence that 3-dimensional (3D) non-adherent conditions are more relevant to the in vivo condition. While one of the criteria for human mesenchymal stem cells (MSCs) has been in vitro plastic adherence, such 2D culture conditions are not representative of in vivo cell-cell and cell-extracellular matrix (ECM) interactions, which may be especially important for this progenitor/stem cell of skeletal and connective tissues. The 3D spheroid, a multicellular aggregate formed under non-adherent 3D in vitro conditions, may be particularly suited as an in vitro method to better understand MSC physiological processes, since expression of ECM and other adhesion proteins are upregulated in such a cell culture system. First used in embryonic stem cell in vitro culture to recapitulate in vivo developmental processes, 3D spheroid culture has grown in popularity as an in vitro method to mimic the 3-dimensionality of the native niche for MSCs within tissues/organs. In this review, we discuss the relevance of the 3D spheroid culture for understanding MSC biology, summarize the biological outcomes reported in the literature based on such this culture condition, as well as contemplate limitations and future considerations in this rapidly evolving and exciting area.

The Risk of Endometrial Cancer and Uterine Sarcoma Following Endometriosis or Pelvic Inflammatory Disease.

The relationship between uterine corpus cancer and endometriosis was conflicting. We aimed to determine the risk of uterine cancer in patients with endometriosis or pelvic inflammatory disease (PID). In this population-based cohort study, a total of 135,236 females with endometriosis (n = 20,510) or PID (n = 114,726), as well as 135,236 age-matched controls, were included. Cox regression models estimated the risk of uterine cancer in each group. Sub-outcomes of risk for uterine corpus cancer included endometrial cancer and uterine sarcoma were analyzed. An age subgroup analysis was performed to determine the moderator effect of age. A landmark analysis depicted the time varying effect of endometriosis and PID. A propensity score matching analysis was conducted to validate the findings. Patients with endometriosis had significantly higher risk of endometrial cancer (adjusted hazard ratio, aHR = 2.92; 95% CI = 2.12-4.03) and uterine sarcoma (aHR = 5.83; 95% CI = 2.02-16.89), while PID was not associated with the risk of uterine cancer. The increased risk of uterine cancer in patients with endometriosis persisted after propensity score matching (aHR = 2.83, 95%CI = 1.70-4.71). The greatest risk of endometrial cancer occurred in patients who had endometriosis for 37 to 60 months (adjusted relative risk, aRR = 9.15, 95% CI = 4.40-19.02). Females aged 12 to 35 years were at the greatest risk of endometriosis-associated uterine cancer (RR = 6.97, 95% CI = 3.41-14.26). In conclusion, patients with endometriosis were at great risk of uterine cancer, including endometrial cancer and uterine sarcoma, compared with propensity score-matched populations and compared with patients of PID. Younger females with endometriosis and patients who had endometriosis for three to five years were at the greatest risk of endometriosis-associated uterine cancer.

Efficacy of adhesive strategies for restorative dentistry: A systematic review and network meta-analysis of double-blind randomized controlled trials over 12 months of follow-up.

PURPOSE: The efficacy of etch-and-rinse, selective enamel-etching, and self-etching protocols for universal adhesives in follow-ups of over 12 months was compared in a network meta-analysis. STUDY SELECTION: Randomized controlled trials (RCTs) published from 1998 to 2022 that compared marginal staining, marginal adaptation, retention and fractures, post-operative sensitivity, or recurrence of caries that took place over 12-months post-restoration were selected. A network meta-analysis determined the performance of each adhesive protocol. RESULTS: After screening 981 articles, 16 RCTs were subjected to data extraction. Of which, 674 patients with 2816 restorations, were included in the network meta-analysis. The pooled risk of marginal discoloration following self-etching was significantly higher than that following etch-and-rinse at over 12, 24, and 36 months, which was time-dependent. The pooled risks of unfavorable marginal adaptation and unfavorable retention and fractures following self-etching were also significantly higher than that following etch-and-rinse, with the rates of unfavorable retention and fractures in non-carious cervical lesions increasing in a time-dependent manner. The pooled risks of marginal discoloration, unfavorable marginal adaptation, retention and fractures were similar between etch-and-rinse and selective enamel-etching protocols. Post-operative hypersensitivity and recurrence of caries were not significantly different among etch-and-rinse, selective enamel-etching, and self-etching protocols. CONCLUSIONS: In follow-ups over 12 months, esthetic and functional outcomes of restorations completed with an etch-and-rinse adhesive protocol were superior to the ones achieved with a self-etching strategy without selective enamel-etching. Selective enamel etching is recommended for self-etching systems. Biological responses were similar for all three adhesive strategies.

Placental mesenchymal stem cells boost M2 alveolar over M1 bone marrow macrophages via IL-1ß in Klebsiella-mediated acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a lethal complication of severe bacterial pneumonia due to the inability to dampen overexuberant immune responses without compromising pathogen clearance. Both of these processes involve tissue-resident and bone marrow (BM)-recruited macrophage (MΦ) populations which can be polarised to have divergent functions. Surprisingly, despite the known immunomodulatory properties of mesenchymal stem cells (MSCs), simultaneous interactions with tissue-resident and recruited BMMΦ populations are largely unexplored. OBJECTIVES: We assessed the therapeutic use of human placental MSCs (PMSCs) in severe bacterial pneumonia with elucidation of the roles of resident alveolar MΦs (AMΦs) and BMMΦs. METHODS: We developed a lethal, murine pneumonia model using intratracheal infection of a clinically relevant Klebsiella pneumoniae (KP) strain with subsequent intravenous human PMSC treatment. Pulmonary AMΦ and recruited BMMΦ analyses, histological evaluation, bacterial clearance and mice survival were assessed. To elucidate the role of resident AMΦs in improving outcome, we performed AMΦ depletion in the KP-pneumonia model with intratracheal clodronate pretreatment. MEASUREMENTS AND MAIN RESULTS: Human PMSC treatment decreased tissue injury and improved survival of severe KP-pneumonia mice by decreasing the presence and function of recruited M1 BMMΦ while preserving M2 AMΦs and enhancing their antibacterial functions. Interestingly, PMSC therapy failed to rescue AMΦ-depleted mice with KP pneumonia, and PMSC-secreted IL-1ß was identified as critical in increasing AMΦ antibacterial activities to significantly improve pathogen clearance-especially bacteraemia-and survival. CONCLUSIONS: Human PMSC treatment preferentially rescued resident M2 AMΦs over recruited M1 BMMΦs with overall M2 polarisation to improve KP-related ARDS survival.

Age-dependent oral manifestations of neurofibromatosis type 1: a case-control study.

INTRODUCTION: Most craniofacial manifestations of neurofibromatosis type 1 (NF1) are considered as a result of tumor compression. We sought to determine salivary changes, caries, and periodontal complications in NF1 patients without tumors in the oral cavity. OBJECTIVE AND METHODS: Eleven NF1 patients without tumors in the oral cavity and 29 matched controls without NF1 were enrolled in this case-control study. Demographic information, medical history, and data of intraoral examinations, including the Decayed, Missing, and Filled Teeth (DMFT) scores and Russel's periodontal index (PI), were recorded. The functional salivary analysis was performed for sialometry, salivary pH values, and amylase activity. Ingenuity Systems Pathway Analysis (IPA) was conducted to identify mutually activated pathways for NF1-associated oral complications. RESULTS: NF1 patients were associated with periodontitis (OR = 1.40, 95% CI = 1.06-1.73, P = 0.04), gingivitis (OR = 1.55, 95% CI = 1.09-2.01, P = 0.0002), and decreased salivary flow rates (OR = 1.40, 95% CI = 1.05-1.76, P = 0.005). Periodontal destruction, salivary changes, and dental caries in NF1 patients were age-dependent. Subgroup analyses based on age stratification suggested that salivary flow rates and salivary amylase activities were significantly low in NF1 patients aged over 20 years and that salivary pH values, PI and DMFT scores were significantly high among NF1- controls aged over 20. All oral complications were not significantly presented in NF1 patients aged below 20 years. IPA analyses suggested that cellular mechanisms underlying NF1-associated oral complications involved chronic inflammatory pathways and fibrosis signaling pathway. CONCLUSION: NF1 patients without tumors in the oral cavity presented a comparatively high prevalence of age-dependent oral complications, including periodontal destruction and salivary gland dysfunction, which were associated with chronic inflammatory pathogenesis.

Patients with juvenile idiopathic arthritis are at increased risk for obstructive sleep apnoea: a population-based cohort study.

BACKGROUND AND OBJECTIVES: Juvenile idiopathic arthritis (JIA), an autoimmune disease, has been proposed to be comorbid with obstructive sleep apnoea (OSA). We aimed at testing the hypothesis that patients with JIA may presented with high risk of OSA in a cohort study. SUBJECTS AND METHODS: This is a cohort study including patients with JIA from 1999 to 2013 identified from a longitudinal health registry. A matched non-JIA control group was also included. The primary outcome variable was presence of OSA. A Cox proportional hazard model was developed to estimate the risk of OSA in patients with JIA. A cumulative probability model was adopted to assess the time-dependent effect of JIA on OSA development, implying a causal link of the association. RESULTS: A total of 2791 patients with JIA were included, and 11 164 individuals without JIA were selected as matched controls. A total of 95 included subjects had OSA: 31 in the JIA group and 64 in the control group. Patients with JIA were more likely to have OSA compared with controls (adjusted hazard ratio, aHR = 1.922, 95% confidence interval [CI] = 1.244-2.970). The incidence of developing OSA was particularly high among patients with JIA-associated deformity that presented at age 18-30 years (aHR = 1.993, 95% CI = 1.277-3.113) and males (aHR = 1.786, 95% CI = 1.097-2.906). The risk of developing OSA increased over 60 months (aHR = 2.523, 95% CI = 1.322-4.815) of follow-up after the JIA diagnosis. CONCLUSIONS: Patients with JIA have a significantly increased risk of developing OSA compared with matched individuals without JIA.

Exposure to environmental air pollutants as a risk factor for primary Sjögren's syndrome.

Background: Environmental etiology of primary Sjögren's syndrome (pSS), an autoimmune disease, has been proposed. This study determined whether the exposure to air pollutants was an independent risk factor for pSS. Methods: Participants were enrolled from a population-based cohort registry. Daily average concentrations of air pollutants from 2000 to 2011 were divided into 4 quartiles. Adjusted hazard ratios (aHRs) of pSS for exposure to air pollutants were estimated in a Cox proportional regression model adjusting for age, sex, socioeconomic status, and residential areas. A subgroup analysis stratified by sex was conducted to validate the findings. Windows of susceptibility indicated years of exposure which contributed the most to the observed association. Ingenuity Pathway Analysis was used to identify underlying pathways of air pollutant-associated pSS pathogenesis, using Z-score visualization. Results: Two hundred patients among 177,307 participants developed pSS, with a mean age of 53.1 years at acumulative incidence of 0.11% from 2000 to 2011. Exposure to carbon monoxide (CO), nitric oxide (NO), and methane (CH4) was associated with a higher risk of pSS. Compared to those exposed to the lowest concentration level, the aHRs for pSS were 2.04 (95%CI=1.29-3.25), 1.86 (95%CI=1.22-2.85), and 2.21 (95%CI=1.47-3.31) for those exposed to high levels of CO, NO, and CH4, respectively. The findings persisted in the subgroup analysis, in which females exposed to high levels of CO, NO, and CH4 and males exposed to high levels of CO were associated with significantly great risk of pSS. The cumulative effect of air pollution on pSS was time-dependent. The underlying cellular mechanisms involved chronic inflammatory pathways including the interleukin-6 signaling pathway. Conclusion: Exposure to CO, NO, and CH4 was associated with a high risk of pSS, which was biologically plausible.

Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials.

Clinical trials evaluating the safety and antibody response of strategies to manipulate prophylactic and therapeutic immunity have been launched. We aim to evaluate strategies for augmentation of host immunity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We searched clinical trials registered at the National Institutes of Health by 25 May 2021 and conducted analyses on inoculated populations, involved immunological processes, source of injected components, and trial phases. We then searched PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials for their corresponding reports published by 25 May 2021. A bivariate, random-effects meta-analysis was used to derive the pooled estimate of seroconversion and adverse events (AEs). A total of 929,359 participants were enrolled in 389 identified trials. The working mechanisms included heterologous immunity, active immunity, passive immunity, and immunotherapy, with 62.4% of the trials on vaccines. A total of 9072 healthy adults from 27 publications for 22 clinical trials on active immunity implementing vaccination were included for meta-analyses. The pooled odds ratios (ORs) of seroconversion were 13.94, 84.86, 106.03, and 451.04 (all p < 0.01) for vaccines based on protein, RNA, viral vector, and inactivated virus, compared with that of respective placebo/control treatment or pre-vaccination sera. The pooled ORs for safety, as defined by the inverse of systemic adverse events (AEs) were 0.53 (95% CI = 0.27-1.05; p = 0.07), 0.35 (95% CI = 0.16-0.75; p = 0.007), 0.32 (95% CI = 0.19-0.55; p < 0.0001), and 1.00 (95% CI = 0.73-1.36; p = 0.98) for vaccines based on protein, RNA, viral vector, and inactivated virus, compared with that of placebo/control treatment. A paradigm shift from all four immune-augmentative interventions to active immunity implementing vaccination was observed through clinical trials. The efficacy of immune responses to neutralize SARS-CoV-2 for these vaccines was promising, although systemic AEs were still evident for RNA-based and viral vector-based vaccines.

Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells.

Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID-19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off-the-shelf products. In addition, new products such as cell-free exosomes and human pluripotent stem cell (hPSC)-derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications-including graft-vs-host-disease, strongly Th17-mediated autoimmune diseases, and osteoarthritis-which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.

Protocol for human placental mesenchymal stem cell therapy in a murine model of intra-abdominal infection of hypervirulent Klebsiella.

Hypervirulent Klebsiella pneumoniae (hvKP) strains cause extra-pulmonary infections such as intra-abdominal infection (IAI) even in healthy individuals due to its resistance to polymorphonuclear neutrophil (PMN) killing and a high incidence of multidrug resistance. To assess whether human placental mesenchymal stem cell (PMSC) therapy can be an effective treatment option, we established a murine model of hvKP-IAI to evaluate immune cell modulation and bacterial clearance for this highly lethal infection. This protocol can rapidly assess potential therapies for severe bacterial IAIs. For complete details on the use and execution of this protocol, please refer to Wang et al. (2020).

Resident vs nonresident multipotent mesenchymal stromal cell interactions with B lymphocytes result in disparate outcomes.

Multipotent human mesenchymal stromal cells (MSCs) from multiple organs including the bone marrow (BM) and placenta harbor clinically relevant immunomodulation best demonstrated toward T lymphocytes. Surprisingly, there is limited knowledge on interactions with B lymphocytes, which originate from the BM where there is a resident MSC. With increasing data demonstrating MSC tissue-specific propensities impacting therapeutic outcome, we therefore investigated the interactions of BM-MSCs-its resident and "niche" MSC-and placental MSCs (P-MSCs), another source of MSCs with well-characterized immunomodulatory properties, on the global functional outcomes of pan-peripheral B cell populations. We found that P-MSCs but not BM-MSCs significantly inhibit proliferation and further differentiation of stimulated human peripheral B populations in vitro. Moreover, although BM-MSCs preserve multiple IL-10-producing regulatory B cell (Breg) subsets, P-MSCs significantly increase all subsets. To corroborate these in vitro findings in vivo, we used a mouse model of B-cell activation and found that adoptive transfer of P-MSCs but not BM-MSCs significantly decreased activated B220+ B cells. Moreover, adoptive transfer of P-MSCs but not BM-MSCs significantly decreased the overall B220+ B-cell proliferation and further differentiation, similar to the in vitro findings. P-MSCs also increased two populations of IL-10-producing murine Bregs more strongly than BM-MSCs. Transcriptome analyses demonstrated multifactorial differences between BM- and P-MSCs in the profile of relevant factors involved in B lymphocyte proliferation and differentiation. Our results highlight the divergent outcomes of tissue-specific MSCs interactions with peripheral B cells, and demonstrate the importance of understanding tissue-specific differences to achieve more efficacious outcome with MSC therapy.