Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 â€‹mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.

Experimental analysis and prediction of radionuclide solubility using machine learning models: Effects of organic complexing agents.

Radioactive wastes contain organic complexing agents that can form complexes with radionuclides and enhance the solubility of these radionuclides, increasing the mobility of radionuclides over great distances from a radioactive waste repository. In this study, four radionuclides (cobalt, strontium, iodine, and uranium) and three organic complexing agents (ethylenediaminetetraacetic acid, nitrilotriacetic acid, and iso-saccharic acid) were selected, and the solubility of these radionuclides was assessed under realistic environmental conditions such as different pHs (7, 9, 11, and 13), temperatures (10 °C, 20 °C, and 40 °C), and organic complexing agent concentrations (10-5-10-2 M). A total of 720 datasets were generated from solubility batch experiments. Four supervised machine learning models such as the Gaussian process regression (GPR), ensemble-boosted trees, artificial neural networks, and support vector machine were developed for predicting the radionuclide solubility. Each ML model was optimized using Bayesian optimization algorithm. The GPR evolved as a robust model that provided accurate predictions within the underlying solubility patterns by capturing the intricate relationships of the independent parameters of the dataset. At an uncertainty level of 95%, both the experimental results and GPR simulated estimations were closely correlated, confirming the suitability of the GPR model for future explorations.

A Waveguide Inline Binary Metasurface for Wavelength-Selective Transmission and Standing Wave Focusing.

This study presents an innovative inline metasurface design for selective wavelength transmission and focusing. When integrated into optical fibers, it improves the stability and compatibility with techniques like wavelength division multiplexing and phase modulation. Precise parameters, determined through analytical calculations and simulations, allow for the design of multifunctional lenses within the optical fiber platform. The numerical results demonstrate unmodulated transmission for specific wavelengths, while others exhibit standing wave focusing with a 0.67 µm beam radius and a 0.31 µm depth of focus. This technology holds promise for applications in quantum experiments, sensing, and optical communication.

P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.

BACKGROUND: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain. METHODS: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro. FINDINGS: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells. INTERPRETATION: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis. FUNDING: This study was supported by a grant from the National Research Foundation of Korea.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Human platelet mitochondria improve the mitochondrial and cardiac function of donor heart.

Mitochondria transplantation emerges as an effective therapeutic strategy for ischemic-related diseases but the roles in the donor hearts for transplant remain unidentified. Here, we investigated whether the preservation of the donor heart with human platelet-derived mitochondria (pl-MT) could improve mitochondrial and cardiac function. Incubation with pl-MT resulted in the internalization of pl-MT and the enhancement of ATP production in primary cardiomyocytes. In addition, incubation of rat hearts with pl-MT ex vivo for 9 h clearly demonstrated pl-MT transfusion into the myocardium. Mitochondria isolated from the hearts incubated with pl-MT showed increased mitochondrial membrane potential and greater ATP synthase activity and citrate synthase activity. Importantly, the production of reactive oxygen species from cardiac mitochondria was not different with and without pl-MT incubation. Functionally, the heartbeat and the volume of coronary circulation perfusate were significantly increased in the Langendorff perfusion system and the viability of cardiomyocytes was increased from pl-MT hearts.Taken together, these results suggest that incubation with Pl-MT improves mitochondrial activity and maintains the cardiac function of rat hearts with prolonged preservation time. The study provides the proof of principle for pl-MT application as an enhancer of the donor heart.

Primary astrocytic mitochondrial transplantation ameliorates ischemic stroke.

Mitochondria are important organelles that regulate adenosine triphosphate production, intracellular calcium buffering, cell survival, and apoptosis. They play therapeutic roles in injured cells via transcellular transfer through extracellular vesicles, gap junctions, and tunneling nanotubes. Astrocytes can secrete numerous factors known to promote neuronal survival, synaptic formation, and plasticity. Recent studies have demonstrated that astrocytes can transfer mitochondria to damaged neurons to enhance their viability and recovery. In this study, we observed that treatment with mitochondria isolated from rat primary astrocytes enhanced cell viability and ameliorated hydrogen peroxide-damaged neurons. Interestingly, isolated astrocytic mitochondria increased the number of cells under damaged neuronal conditions, but not under normal conditions, although the mitochondrial transfer efficiency did not differ between the two conditions. This effect was also observed after transplanting astrocytic mitochondria in a rat middle cerebral artery occlusion model. These findings suggest that mitochondria transfer therapy can be used to treat acute ischemic stroke and other diseases. [BMB Reports 2023; 56(2): 90-95].

BMPR1A promotes ID2-ZEB1 interaction to suppress excessive endothelial to mesenchymal transition.

AIMS: Components of bone morphogenetic protein (BMP) signalling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP type 2 receptor in these processes has been extensively analysed. However, the contribution of BMP type 1 receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be down-regulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH. METHODS AND RESULTS: We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a-deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs towards transforming growth factor beta (TGFß) stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH. CONCLUSIONS: We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signalling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.

Platelet-derived mitochondria transfer facilitates wound-closure by modulating ROS levels in dermal fibroblasts.

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing in vitro using a cell-based model. Wound repairs were assessed by 2D gap closure experiment in wound scratch assay using human dermal fibroblasts (hDFs). Results demonstrated that pl-MT were successfully internalized into hDFs. It increased cell proliferation and promoted the closure of wound gap. Importantly, pl-MT suppressed both intracellular and mitochondrial ROS production induced by hydrogen peroxide, cisplatin, and TGF-ß in hDFs. Taken together, these results suggest that pl-MT transfer might be used as a potential therapeutic strategy for wound repair.

What is the context? During the wound healing process, abnormal regulation of ROS and inflammation delays the healing process, resulting in chronic non-healing wounds.Mitochondria are key organelles responsible for the ROS generation. Mitochondrial dysfunction has been implicated in delayed wound repair.Mitochondria transfer, which utilizes intact mitochondria isolated from healthy cells to recover from disease, has been applied in various clinical studies, but additional evidence is needed to apply it to wound healing.What is new? In this study, we chose platelets as a cell source for mitochondrial transfer. We isolated the functional mitochondria from platelets and applied them to wound healing.What is the impact? This study provides evidence that platelet-derived mitochondria (pl-MT) improve the wound healing progress by increasing the viability of dermal fibroblasts and suppressing intracellular and mitochondrial ROS production.Platelets have also been demonstrated to be a suitable cell source for mitochondrial transfer.

Endothelial ß-arrestins regulate mechanotransduction by the type II bone morphogenetic protein receptor in primary cilia.

Modulation of endothelial cell behavior and phenotype by hemodynamic forces involves many signaling components, including cell surface receptors, intracellular signaling intermediaries, transcription factors, and epigenetic elements. Many of the signaling mechanisms that underlie mechanotransduction by endothelial cells are inadequately defined. Here we sought to better understand how ß-arrestins, intracellular proteins that regulate agonist-mediated desensitization and integration of signaling by transmembrane receptors, may be involved in the endothelial cell response to shear stress. We performed both in vitro studies with primary endothelial cells subjected to ß-arrestin knockdown, and in vivo studies using mice with endothelial specific deletion of ß-arrestin 1 and ß-arrestin 2. We found that ß-arrestins are localized to primary cilia in endothelial cells, which are present in subpopulations of endothelial cells in relatively low shear states. Recruitment of ß-arrestins to cilia involved its interaction with IFT81, a component of the flagellar transport protein complex in the cilia. ß-arrestin knockdown led to marked reduction in shear stress response, including induction of NOS3 expression. Within the cilia, ß-arrestins were found to associate with the type II bone morphogenetic protein receptor (BMPR-II), whose disruption similarly led to an impaired endothelial shear response. ß-arrestins also regulated Smad transcription factor phosphorylation by BMPR-II. Mice with endothelial specific deletion of ß-arrestin 1 and ß-arrestin 2 were found to have impaired retinal angiogenesis. In conclusion, we have identified a novel role for endothelial ß-arrestins as key transducers of ciliary mechanotransduction that play a central role in shear signaling by BMPR-II and contribute to vascular development.

Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction. In this study, the migration of mitochondria was tracked in vitro and in vivo using mitochondria conjugated with green fluorescent protein (MTGFP). When MTGFP were used in a coculture model, they were selectively internalized into lung fibroblasts, and this selectivity depended on the mitochondrial functional states of the receiving fibroblasts. Compared with MTGFP injected intravenously into normal mice, MTGFP injected into bleomycin-induced idiopathic pulmonary fibrosis model mice localized more abundantly in the lung tissue, indicating that mitochondrial homing to injured tissue occurred. This study shows for the first time that exogenous mitochondria are preferentially trafficked to cells and tissues in which mitochondria are damaged, which has implications for the delivery of therapeutic agents to injured or diseased sites.

LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis.

BACKGROUND: Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism. METHODS: Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo. RESULTS: Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis. CONCLUSIONS: Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM.

Epidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia-Induced Lung Injury.

Aims: Studies have linked severe hyperoxia, or prolonged exposure to very high oxygen levels, with worse clinical outcomes. This study investigated the role of epidermal growth factor receptor (EGFR) in hyperoxia-induced lung injury at very high oxygen levels (>95%). Results: Effects of severe hyperoxia (100% oxygen) were studied in mice with genetically inhibited EGFR and wild-type littermates. Despite the established role of EGFR in lung repair, EGFR inhibition led to improved survival and reduced acute lung injury, which prompted an investigation into this protective mechanism. Endothelial EGFR genetic knockout did not confer protection. EGFR inhibition led to decreased levels of cleaved caspase-3 and poly (ADP-ribosyl) polymerase (PARP) and decreased terminal dUTP nick end labeling- (TUNEL-) positive staining in alveolar epithelial cells and reduced ERK activation, which suggested reduced apoptosis in vivo. EGFR inhibition decreased hyperoxia (95%)-induced apoptosis and ERK in murine alveolar epithelial cells in vitro, and CRISPR-mediated EGFR deletion reduced hyperoxia-induced apoptosis and ERK in human alveolar epithelial cells in vitro. Innovation. This work defines a protective role of EGFR inhibition to decrease apoptosis in lung injury induced by 100% oxygen. This further characterizes the complex role of EGFR in acute lung injury and outlines a novel hyperoxia-induced cell death pathway that warrants further study. Conclusion: In conditions of severe hyperoxia (>95% for >24 h), EGFR inhibition led to improved survival, decreased lung injury, and reduced cell death. These findings further elucidate the complex role of EGFR in acute lung injury.

Erratum to: Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

[Erratum to: BMB Reports 2022; 55(3): 136-141, PMID: 34488927, PMCID: PMC8972135] The BMB Reports would like to correct in BMB Rep. 55(3):136-141, titled "Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway". This research was supported by NRF-2016R1A2B4007640 grant (to C-H Kim). Since grant number is incorrect, this information has now been corrected as follows: We would like to thank various Paean Biotechnology Inc. members who participated in the project. This work was supported by NRF-2018M3A9B5023055 grant (to C-H Kim). The authors apologize for any inconvenience or confusion that may be caused by this error. The ACKNOWLEDGEMENTS of Original PDF version have been corrected.

Efficient gene transfection to lung cancer cells via Folate-PEI-Sorbitol gene transporter.

Lung cancer is known to be one of the fatal diseases in the world and is experiencing treatment difficulties. Many treatments have been discovered and implemented, but death rate of patients with lung cancer continues to remain high. Current treatments for cancer such as chemotherapy, immunotherapy, and radiotherapy have shown considerable results, yet they are accompanied by side effects. One effective method for reducing the cytotoxicity of these treatments is via the use of a nanoparticle-mediated siRNA delivery strategy with selective silencing effects and non-viral vectors. In this study, a folate (FA) moiety ligand-conjugated poly(sorbitol-co-PEI)-based gene transporter was designed by combining low-molecular weight polyethyleneimine (LMW PEI) and D-sorbitol with FA to form FPS. Since folate receptors are commonly overexpressed in various cancer cells, folate-conjugated nanoparticles may be more effectively delivered to selective cancer cells. Additionally, siOPA1 was used to induce apoptosis through mitochondrial fusion. The OPA1 protein stability level is important for maintaining normal mitochondrial cristae structure and function, conserving the inner membrane structure, and protecting cells from apoptosis. Consequently, when FPS/siOPA1 was used for lung cancer in-vitro and in-vivo, it improved cell viability and cellular uptake.

Association of renalase with clinical outcomes in hospitalized patients with COVID-19.

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March-June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if <18 years, or opted out of research. The primary composite outcome was intubation or death within 180 days. Secondary outcomes included mortality alone, intensive care unit admission, use of vasopressors, and CPR. Enrolled patients had mean age 64 years (SD±17), were 53% males, and 48% non-whites. Mean renalase levels was 14,108·4 ng/ml (SD±8,137 ng/ml). Compared to patients with high renalase, those with low renalase (< 8,922 ng/ml) were more likely to present with hypoxia, increased ICU admission (54% vs. 33%, p < 0.001), and cardiopulmonary resuscitation (10% vs. 4%, p = 0·023). In Cox proportional hazard model, every 1000 ng/ml increase in renalase decreased the risk of death or intubation by 5% (HR 0·95; 95% CI 0·91-0·98) and increased survival alone by 6% (HR 0·95; CI 0·90-0·98), after adjusting for socio-demographics, initial disease severity, comorbidities and inflammation. Patients with high renalase-low IL-6 levels had the best survival compared to other groups (p = 0·04). Renalase was independently associated with reduced intubation and mortality in hospitalized COVID-19 patients. Future studies should assess the pathophysiological relevance of renalase in COVID-19 disease.

Macrophage IL-1ß promotes arteriogenesis by autocrine STAT3- and NF-κB-mediated transcription of pro-angiogenic VEGF-A.

Peripheral artery disease (PAD) leads to considerable morbidity, yet strategies for therapeutic angiogenesis fall short of being impactful. Inflammatory macrophage subsets play an important role in orchestrating post-developmental angiogenesis, but the underlying mechanisms are unclear. Here, we find that macrophage VEGF-A expression is dependent upon the potent inflammatory cytokine, IL-1ß. IL-1ß promotes pro-angiogenic VEGF-A165a isoform transcription via activation and promoter binding of STAT3 and NF-κB, as demonstrated by gene-deletion, gain-of-function, inhibition, and chromatin immunoprecipitation assays. Conversely, IL-1ß-deletion or inhibition of STAT3 or NF-κB increases anti-angiogenic VEGF-A165b isoform expression, indicating IL-1ß signaling may also direct splice variant selection. In an experimental PAD model of acute limb ischemia, macrophage IL-1ß expression is required for pro-angiogenic VEGF-A expression and for VEGF-A-induced blood flow recovery via angio- or arteriogenesis. Though further study is needed, macrophage IL-1ß-dependent transcription of VEGF-A via STAT3 and NF-κB may have potential to therapeutically promote angiogenesis in the setting of PAD.

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could significantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses. [BMB Reports 2022; 55(3): 136-141].

LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming.

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.