The unique immunomodulatory properties of mesenchymal stem cells (MSCs) make them an invaluable cell type for the repair of tissue/ organ damage caused by chronic inflammation or autoimmune disorders. Although they hold great promise in the treatment of immune disorders such as graft versus host disease (GvHD) and allergic disorders, there remain many challenges to overcome before their widespread clinical application. An understanding of the biological properties of MSCs will clarify the mechanisms of MSC-based transplantation for immunomodulation. In this review, we summarize the preclinical and clinical studies of MSCs from different adult tissues, discuss the current hurdles to their use and propose the future development of pluripotent stem cell-derived MSCs as an approach to immunomodulation therapy.

Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.Key words: Mesenchymal stem cells (MSCs); Mechanism; Paracrine effects effective cell source in cell-based treatment. The fascinating therapeutic effects of MSCs in various life-threatening human diseases, including cerebral spinal cord injury, hematological disorders, cardiovascular diseases, diabetes, immune diseases, graft versus host diseases (GvHDs), and cancer, are well documented. Nonetheless, the indepth mechanisms of how MSCs act remain a matter for debate and exploration. The generally putative concepts cover transdifferentiation, cell fusion, paracrine effects, microvesicles carrying messenger RNA (mRNA) or microRNA (miRNA) and mitochondrial transfer (Fig. 1) (8,9,16,31,34,35,43,97,101,136). This review will focus on the paracrine effects of MSCs, the most comprehensive and enduring mode of action that ascribes to functional recovery in both acute and chronic responses.

Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.

SummaryMesenchymal stem cells (MSCs) can donate mitochondria and rescue anthracycline-induced cardiomyocyte (CM) damage, although the underlying mechanisms remain elusive. We determined that the superior efficiency of mitochondrial transfer by human induced-pluripotent-stem-cell-derived MSCs (iPSC-MSCs) compared with bone marrow-derived MSCs (BM-MSCs) is due to high expression of intrinsic Rho GTPase 1 (MIRO1). Further, due to a higher level of TNFαIP2 expression, iPSC-MSCs are more responsive to tumor necrosis factor alpha (TNF-α)-induced tunneling nanotube (TNT) formation for mitochondrial transfer to CMs, which is regulated via the TNF-α/NF-κB/TNFαIP2 signaling pathway. Inhibition of TNFαIP2 or MIRO1 in iPSC-MSCs reduced the efficiency of mitochondrial transfer and decreased CMs protection. Compared with BM-MSCs, transplantation of iPSC-MSCs into a mouse model of anthracycline-induced cardiomyopathy resulted in more human mitochondrial retention and bioenergetic preservation in heart tissue. Efficacious transfer of mitochondria from iPSC-MSCs to CMs, due to higher MIRO1 expression and responsiveness to TNF-α-induced nanotube formation, effectively attenuates anthracycline-induced CM damage.

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disorder, and increases in prevalence with increasing age and the number of cardiovascular comorbidities. AF is characterized by a rapid and irregular heartbeat that can be asymptomatic or lead to symptoms such as palpitations, dyspnoea and dizziness. The condition can also be associated with serious complications, including an increased risk of stroke. Important recent developments in the clinical epidemiology and management of AF have informed our approach to this arrhythmia. This Primer provides a comprehensive overview of AF, including its epidemiology, mechanisms and pathophysiology, diagnosis, screening, prevention and management. Management strategies, including stroke prevention, rate control and rhythm control, are considered. We also address quality of life issues and provide an outlook on future developments and ongoing clinical trials in managing this common arrhythmia.

BackgroundElevated lipoprotein-associated phospholipase A 2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A 2 . MethodsIn a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). ResultsDuring a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P = 0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P = 0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P = 0.02). ConclusionsIn patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.)The Darapladib is a potent and reversible oral inhibitor of lipoprotein-associated phospholipase A 2 . 10 In a swine model of atherosclerosis, darapladib reduced levels of lipoprotein-associated phospholipase A 2 in plaque, reduced the necrotic core area, and inhibited the development of lesions in coronary arteries. 11 Darapladib has also been shown to reduce lipoprotein-associated phospholipase A 2 activity in human carotid plaque. 12 In the Integrated Biomarker and Imaging Study 2 (IBIS-2) involving patients with coronary heart disease, darapladib, as compared with placebo, halted the progression in the volume of the necrotic core of coronary-artery plaques (a secondary end point), as determined by intravascular ultrasonographic virtual histologic analysis during a 12-month period. 13 These findings suggest that darapladib could reduce the risk of events associated with coronary heart disease by altering the composition of atherosclerotic plaques to a less vulnerable state. 1 In the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial, we evaluated the clini...

Recent studies have demonstrated that mesenchymal stem cells (MSCs) can donate mitochondria to airway epithelial cells and rescue mitochondrial damage in lung injury. We sought to determine whether MSCs could donate mitochondria and protect against oxidative stress-induced mitochondrial dysfunction in the cornea. Co-culturing of MSCs and corneal epithelial cells (CECs) indicated that the efficiency of mitochondrial transfer from MSCs to CECs was enhanced by Rotenone (Rot)-induced oxidative stress. The efficient mitochondrial transfer was associated with increased formation of tunneling nanotubes (TNTs) between MSCs and CECs, tubular connections that allowed direct intercellular communication. Separation of MSCs and CECs by a transwell culture system revealed no mitochiondrial transfer from MSCs to CECs and mitochondrial function was impaired when CECs were exposed to Rot challenge. CECs with or without mitochondrial transfer from MSCs displayed a distinct survival capacity and mitochondrial oxygen consumption rate. Mechanistically, increased filopodia outgrowth in CECs for TNT formation was associated with oxidative inflammation-activated NFκB/TNFαip2 signaling pathways that could be attenuated by reactive oxygen species scavenger N-acetylcysteine (NAC) treatment. Furthermore, MSCs grown on a decellularized porcine corneal scaffold were transplanted onto an alkali-injured eye in a rabbit model. Enhanced corneal wound healing was evident following healthy MSC scaffold transplantation. And transferred mitochondria was detected in corneal epithelium. In conclusion, mitochondrial transfer from MSCs provides novel protection for the cornea against oxidative stress-induced mitochondrial damage. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.

Objective-Serum levels of fibroblast growth factor-21 (FGF21), a metabolic hormone, have been shown to be elevated in subjects with adverse lipid profiles, obesity, metabolic syndrome, impaired glucose tolerance, type 2 diabetes mellitus, and hypertension. Recently, elevated serum FGF21 levels have also been reported in subjects with coronary heart disease or carotid artery plaques. However, whether serum FGF21 is independently associated with atherosclerotic diseases remains unclear. In this study, we examined the relationship between serum FGF21 levels and carotid intima-media thickness (IMT) in a large cohort of Southern Chinese subjects. Approach and Results-The cohort consisted of 670 subjects who underwent carotid IMT measurement. Serum FGF21 levels were measured with an ELISA kit. Serum FGF21 levels positively correlated with carotid IMT in women (r=0.32; P<0.001), but not in men (r=0.06; P=0.305). On multiple linear regression analysis, elevated serum FGF21 level in women was an independent risk factor for increased carotid IMT (P=0.039), together with age (P<0.001) and hypertension (P=0.011), in a model comprising also waist circumference, smoking history, serum creatinine, high sensitive C-reactive protein, dysglycemia, and dyslipidemia (adjusted R 2 =35.8%; P<0.001). Elevated serum FGF21 levels were also a significant independent risk factor of carotid IMT on multiple stepwise regression analysis (P=0.01). with type 2 DM. 12,13 However, whether serum FGF21 is independently associated with atherosclerotic diseases remains unclear. To evaluate the relationship between serum FGF21 levels and atherosclerosis, we examined in 670 Southern Chinese subjects with no overt macrovascular disease the association between serum FGF21 levels and carotid intima-media thickness (IMT), a well-established marker of atherosclerosis. Conclusions-The14 Established cardiovascular risk factors and high sensitive C-reactive protein (CRP) were also measured to determine whether FGF21 is an independent risk factor for increased carotid IMT. Materials and MethodsMaterials and Methods are available in the online-only Supplement. ResultsThe demographic and biochemical characteristics of the subjects are summarized in Table 1. Of the 502 subjects recruited from the third assessment of the Hong Kong Cardiovascular Risk Factor Prevalence Study, 262, 128, and 112 had normal glucose tolerance, impaired glucose tolerance (IGT)/impaired fasting glucose (IFG) and DM, respectively. In all, 176 (26.3%) and 76 (11.3%) of the 670 subjects were on antidiabetic and lipid-lowering medications, respectively. The former group comprised 109 metformin-treated subjects. For the use of peroxisome proliferator-activated receptors agonists, 20 subjects of the entire cohort were treated with fibrates and none of them was on thiazolidinediones. For these treatment modalities, there were no between-group differences in serum FGF21 levels based on analysis in which subjects were stratified according to the use of medication.Among subjects with different gl...