Self-Organization of Sinusoidal Vessels in Pluripotent Stem Cell-derived Human Liver Bud Organoids.

The induction of tissue-specific vessels in in vitro living tissue systems remains challenging. Here, we directly differentiated human pluripotent stem cells into CD32b+ putative liver sinusoidal progenitors (iLSEP) by dictating developmental pathways. By devising an inverted multilayered air-liquid interface (IMALI) culture, hepatic endoderm, septum mesenchyme, arterial and sinusoidal quadruple progenitors self-organized to generate and sustain hepatocyte-like cells neighbored by divergent endothelial subsets composed of CD32blowCD31high, LYVE1+STAB1+CD32bhighCD31lowTHBD-vWF-, and LYVE1-THBD+vWF+ cells. Wnt2 mediated sinusoidal-to-hepatic intercellular crosstalk potentiates hepatocyte differentiation and branched endothelial network formation. Intravital imaging revealed iLSEP developed fully patent human vessels with functional sinusoid-like features. Organoid-derived hepatocyte- and sinusoid-derived coagulation factors enabled correction of in vitro clotting time with Factor V, VIII, IX, and XI deficient patients' plasma and rescued the severe bleeding phenotype in hemophilia A mice upon transplantation. Advanced organoid vascularization technology allows for interrogating key insights governing organ-specific vessel development, paving the way for coagulation disorder therapeutics.

Laparoscopic partial splenectomy in a patient with splenic hemangioma after distal gastrectomy for a neuroendocrine tumor.

Herein, we report the case of a patient with splenic hemangioma after distal gastrectomy who was treated with laparoscopic partial splenectomy. A 64-year-old woman previously underwent laparoscopic distal gastrectomy with regional lymph-node dissection for a gastric neuroendocrine tumor (G3) with venous infiltration and no lymph-node metastases. Periodic follow-up abdominal computed tomography revealed a well-defined, heterogeneous mass in the lower pole of the spleen 5 years after the operation, which grew from 12 to 19 mm 1 year later. A laparoscopic partial splenectomy was planned. During surgery, a smooth-surfaced mass with a lighter color than that of the surrounding area was observed at the lower pole of the spleen. The inferior polar branch of the splenic artery was transected, and the ischemic area of the lower pole of the spleen, where the tumor was present, was confirmed. First, the line used to perform splenic transection was determined using soft coagulation. The splenic parenchyma was then gradually transected using a vessel-sealing device system, and partial splenectomy was possible with almost no bleeding. The patient was discharged on postoperative day 8 without any complications. Pathological examination revealed a hemangioma without any malignant findings. Laparoscopic partial splenectomy is a safe and useful procedure that can be performed, considering the tumor size and location.

Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury.

Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuron-restrictive silencer factor represses mu opioid receptor (MOP) gene expression in the dorsal root ganglion (DRG) via histone hypoacetylation-mediated mechanisms after peripheral nerve injury, thereby causing loss of peripheral morphine analgesia. Here, we showed that histone deacetylase (HDAC) inhibitors, such as trichostatin A and valproic acid, restored peripheral and systemic morphine analgesia in neuropathic pain. Also, these agents blocked nerve injury-induced MOP down-regulation in the DRG. These results suggest that HDAC inhibitors could serve as adjuvant analgesics to morphine for the management of neuropathic pain.

HDAC inhibitors restore C-fibre sensitivity in experimental neuropathic pain model.

BACKGROUND AND PURPOSE: Hypoesthesia is a clinical feature of neuropathic pain. The feature is partly explained by the evidence of epigenetic repression of Nav 1.8 sodium channel in the dorsal root ganglion (DRG). EXPERIMENTAL APPROACH: We investigated the possibility of trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to reverse the unique C-fibre sensitivity observed following partial ligation of sciatic nerve in mice. KEY RESULTS: Nerve injury-induced down-regulation of DRG Nav 1.8 sodium channel and C-fibre-related hypoesthesia were reversed by TSA, VPA and SAHA treatments, which inhibit histone deacetylase (HDAC), and increase histone acetylation at the regulatory sequence of Nav 1.8. CONCLUSIONS AND IMPLICATIONS: Taken together, these studies provide the evidence that hypoesthesia and underlying down-regulation of Nav 1.8, negative symptoms observed in nerve injury-induced neuropathic pain models are regulated by an epigenetic chromatin remodelling through HDAC-related machineries.

Permanent relief from intermittent cold stress-induced fibromyalgia-like abnormal pain by repeated intrathecal administration of antidepressants.

BACKGROUND: Fibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS). RESULTS: In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief. CONCLUSIONS: These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.