Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates

Differentiation of embryonic or determined stem cell populations to adult liver fates under known conditions yields cells with some but not other adult-specific genes, aberrant regulation of one or more genes, and variation in the results from experiment to experiment. We tested the hypothesis that sets of signals produced by freshly isolated, lineage-dependent mesenchymal cell populations would yield greater efficiency and reproducibility in driving differentiation of human hepatic stem cells (hHpSCs) to adult liver fates. Subpopulations of liver-derived mesenchymal cells, purified by immunoselection technologies, included 1) angioblasts; 2) mature endothelia; 3) hepatic stellate cell precursors; 4) mature stellate cells (pericytes) and 5) myofibroblasts. Freshly immunoselected cells of each of these subpopulations were established in primary cultures under wholly defined (serum-free) conditions that we developed for short-term cultures and used them as feeders with hHpSCs. Feeders of angioblasts yielded self-replication; stellate cell precursors caused lineage restriction to hepatoblasts; mature endothelia produced differentiation to hepatocytes; and mature stellate cells and/or myofibroblasts resulted in differentiation to cholangiocytes. Paracrine signals, produced by the different feeders, were identified by biochemical, immunohistochemical, and qRT-PCR analyses and then those signals were used to replace the feeders in monolayer and 3-D cultures to elicit the desired biological responses from the hHpSCs. The defined paracrine signals proved able to yield reproducible responses from the hHpSCs and to permit differentiation to fully mature and functional parenchymal cells

Concise review: Clinical programs of stem cell therapies for liver and pancreas: Stem Cell Therapies for Liver and Pancreas

Regenerative medicine is transitioning into clinical programs using stem/progenitor cell therapies for repair of damaged organs. We summarize those for liver and pancreas, organs that share endodermal stem cell populations, biliary tree stem cells (hBTSCs), located in peribiliary glands. They are precursors to hepatic stem/progenitors in canals of Hering and to committed progenitors in pancreatic duct glands. They give rise to maturational lineages along a radial axis within bile duct walls and a proximal-to-distal axis starting at the duodenum and ending with mature cells in the liver or pancreas. Clinical trials have been ongoing for years assessing effects of determined stem cells (fetal-liver-derived hepatic stem/progenitors) transplanted into the hepatic artery of patients with various liver diseases. Immunosuppression was not required. Control subjects, those given standard of care for a given condition, all died within a year or deteriorated in their liver functions. Subjects transplanted with 100-150 million hepatic stem/progenitor cells had improved liver functions and survival extending for several years. Full evaluations of safety and efficacy of transplants are still in progress. Determined stem cell therapies for diabetes using hBTSCs remain to be explored but are likely to occur following ongoing preclinical studies. In addition, mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) are being used for patients with chronic liver conditions or with diabetes. MSCs have demonstrated significant effects through paracrine signaling of trophic and immunomodulatory factors, and there is limited evidence for inefficient lineage restriction into mature parenchymal or islet cells. HSCs' effects are primarily via modulation of immune mechanisms

Biliary tree stem cells, precursors to pancreatic committed progenitors: Evidence for possible life-long pancreatic organogenesis: Biliary Tree Stem Cells, Precursors to Pancreatic Committed Progenitors

Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG,OCT4,SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9,SOX17,PDX1,LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3,MUC6,insulin). Radial-axis lineages start in PBGs near the ducts’ fibromuscular layers with stem cells and end at the ducts’ lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes

Human Fetal Liver Stromal Cells That Overexpress bFGF Support Growth and Maintenance of Human Embryonic Stem Cells

In guiding hES cell technology toward the clinic, one key issue to be addressed is to culture and maintain hES cells much more safely and economically in large scale. In order to avoid using mouse embryonic fibroblasts (MEFs) we isolated human fetal liver stromal cells (hFLSCs) from 14 weeks human fetal liver as new human feeder cells. hFLSCs feeders could maintain hES cells for 15 passages (about 100 days). Basic fibroblast growth factor (bFGF) is known to play an important role in promoting self-renewal of human embryonic stem (hES) cells. So, we established transgenic hFLSCs that stably express bFGF by lentiviral vectors. These transgenic human feeder cells — bFGF-hFLSCs maintained the properties of H9 hES cells without supplementing with any exogenous growth factors. H9 hES cells culturing under these conditions maintained all hES cell features after prolonged culture, including the developmental potential to differentiate into representative tissues of all three embryonic germ layers, unlimited and undifferentiated proliferative ability, and maintenance of normal karyotype. Our results demonstrated that bFGF-hFLSCs feeder cells were central to establishing the signaling network among bFGF, insulin-like growth factor 2 (IGF-2), and transforming growth factor β (TGF-β), thereby providing the framework in which hES cells were instructed to self-renew or to differentiate. We also found that the conditioned medium of bFGF-hFLSCs could maintain the H9 hES cells under feeder-free conditions without supplementing with bFGF. Taken together, bFGF-hFLSCs had great potential as feeders for maintaining pluripotent hES cell lines more safely and economically

Research on Control Strategy of High-Speed Grid-Connected FESS (Flywheel Energy Storage System) Based on Dual-PWM Converter

FESS (flywheel energy storage system) motor is used in important load fields for instance rail transit; meanwhile the power flow is formed through the connection between FESS (flywheel energy storage system) and power grid system, which can critically improve the power flow fluctuation caused by new energy grid integration regarding wind and photovoltaic generation concerning that the motor speed in FESS is related to its energy storage capacity. Aiming at the limitation of current low motor speed in the FESS, this article puts forward a high-speed grid-connected FESS, and designs a model via the proposed dual-PWM two-stage control form, which is named as double closed-loop control. In this article, the FESS, as well as the power grid system, is analyzed and simulated in three stages: charging, pre-grid connection and grid connection. In this way, the flywheel motor speed and DC bus voltage signal are sampled to design the flywheel motor side with the proposed method. Then the grid-connected double closed-loop control method is designed for the sampling observation points, which realizes the efficient design on the control strategy of proposed high-speed grid-connected FESS and the verification of voltage and current parameters. The simulation experiments show that the operation process of the grid-connected FESS motor obtains its rapid speed response characteristic, which can meet the proposed design requirements during the charging and discharging process

Nitrogen-Enriched Carbon Nanofibers Derived from Polyaniline and Their Capacitive Properties

Nitrogen-doped carbon materials derived from N-containing conducting polymer have attracted significant attention due to their special electrochemical properties in the past two decades. Novel nitrogen-enriched carbon nanofibers (NCFs) have been prepared by one-step carbonization of p-toluene sulfonic acid (P-TSA) doped polyaniline (PANI) nanofibers, which are successfully synthesized via the rapid mixing oxidative polymerization at room temperature. NCFs with diameters ranging from 100 nm to 150 nm possess a highly specific surface area of 915 m2 g−1 and a relatively rich nitrogen content of 7.59 at %. Electrochemical measurements demonstrate that NCFs have high specific capacitance (172 F g−1, 2 mV s−1) and satisfactory cycling stability (89% capacitance retention after 5000 cycles). The outstanding properties affirm that NCFs can be promising candidates for supercapacitor electrode materials. Interestingly, the carbonization of PANI opens the possibility to tailor the morphology of resulting nitrogen-enriched carbon materials by controlling the reaction conditions of PANI synthesis

Statistical properties of solar Hα flare activity

Magnetic field structures on the solar atmosphere are not symmetric distribution in the northern and southern hemispheres, which is an important aspect of quasi-cyclical evolution of magnetic activity indicators that are related to solar dynamo theories. Three standard analysis techniques are applied to analyze the hemispheric coupling (north-south asymmetry and phase asynchrony) of monthly averaged values of solar Hα flare activity over the past 49 years (from 1966 January to 2014 December). The prominent results are as follows: (1) from a global point of view, solar Hα flare activity on both hemispheres are strongly correlated with each other, but the northern hemisphere precedes the southern one with a phase shift of 7 months; (2) the long-range persistence indeed exists in solar Hα flare activity, but the dynamical complexities in the two hemispheres are not identical; (3) the prominent periodicities of Hα flare activity are 17 years full-disk activity cycle and 11 years Schwabe solar cycle, but the short- and mid-term periodicities cannot determined by monthly time series; (4) by comparing the non-parametric rescaling behavior on a point-by-point basis, the hemispheric asynchrony of solar Hα flare activity are estimated to be ranging from several months to tens of months with an average value of 8.7 months. The analysis results could promote our knowledge on the long-range persistence, the quasi-periodic variation, and the hemispheric asynchrony of solar Hα flare activity on both hemispheres, and possibly provide valuable information for the hemispheric interrelation of solar magnetic activity