大野 伸彦

BACKGROUND: Podocyte infolding glomerulopathy (PIG) is a rare glomerular disease, with case reports and cohort studies lacking clear morphological diagnostic criteria. We aimed to establish transmission electron microscopy (TEM)-based diagnostic criteria for PIG and classify its morphological subtypes. METHODS: This retrospective nationwide cohort study was conducted by the PIG Working Group of the Japanese Society of Nephrology. Clinical data and TEM findings were collected from patients diagnosed with or suspected of PIG at 69 institutions across Japan between 1991-2025. PIG was defined by TEM as podocyte infolding exceeding half the glomerular basement membrane (GBM) thickness at two or more sites within a single capillary loop or the presence of microspheres or microtubules within the GBM. Cases were classified into morphological subtypes, and their clinical characteristics were analyzed. RESULTS: Among 103 registered cases, 93 met diagnostic criteria. Four morphological subtypes were identified: Type A, primary podocyte infolding without prominent microspheres or microtubules (n = 21); Type B, predominant microspheres (n = 34); Type C, microtubules with or without microspheres (n = 38); and Type D, dense clusters of microspheres (n = 10). Types B and C were more common in younger females and frequently associated with systemic lupus erythematosus (58% and 71%, respectively), whereas Types A and D occurred mainly in older males and were not associated with SLE. CONCLUSIONS: We established TEM-based diagnostic criteria for PIG and identified four morphological subtypes, suggesting two clinicopathological phenotypes: SLE-associated (B and C) and non-SLE-associated (A and D).

Memories leave lasting physical changes at the synaptic level. Although stable, larger spines are thought to support memory, the high turnover of dendritic spines and the drifting of neuronal representations after memory formation suggest alternative possibilities. To elucidate the structural trace underlying memory retention, we used a mouse model of artificial hibernation. During hibernation, hippocampal neurons exhibited a substantial reduction in their activity and an extensive elimination of dendritic spines and synapses. Despite these changes, their memory and associated hippocampal neuronal representations remained intact. We found that a subset of spines characterized by synaptic contacts with multisynaptic boutons is maintained during hibernation. These findings suggest that synaptic engram architecture, rather than larger spines per se, is resilient to network remodeling and associated with long-term memory retention.

Mossy fiber (MF)-CA3 synapses in the hippocampus play vital roles in learning and memory. MFs have characteristic giant boutons with thorny excrescences on the dendrites of CA3 pyramidal neurons. The mechanisms underlying the development of this complex synaptic specialization remain unclear. In the present study, the loss of synaptosomal-associated protein 25 (SNAP25)-a protein essential for regulated synaptic vesicular release-increased the density but decreased the size of MF boutons and altered the postsynaptic distribution of homer scaffolding protein 1. Three-dimensional correlative light and electron microscopy revealed that although axon targeting and synapse formation were unaffected, excrescences failed to develop in MF boutons, resulting in a smaller contact area between MF boutons and CA3 dendrites. Moreover, SNAP25-deficient boutons displayed abnormal intracellular profiles, such as the accumulation of large synaptic vesicles. These findings indicate that presynaptic SNAP25 is essential for the maturation and maintenance of specialized hippocampal giant boutons.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation nonhuman primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography (FMERG), we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post-transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

The molecular mechanisms underlying metastasis still remain unclear. We previously established a suspension culture using low-attachment culture dishes and demonstrated that cell lines adapted through 2 months suspension culture (termed FL sublines) exhibited higher metastatic potential than their parental counterparts. In this study, we identified the molecules involved in acquiring these phenotypes under low-adhesion conditions. We showed that detached tumor cells in suspension culture formed spheroids that recapitulated tumor cells in the spread-through-air space (STAS), and demonstrated that the anti-adhesion molecule mucin 21 was upregulated in detached lung cancer cells independent of driver mutations. Analyses of both cell lines and primary tumors revealed that mucin 21 is overexpressed in terminal respiratory unit-type lung adenocarcinomas. Mucin 21-knockout cells showed reduced viability and proliferation under adherent and low-attachment conditions, accompanied by enhanced anoikis. Transmission electron microscopy revealed that the intercellular spaces observed in FL sublines during suspension culture were reduced in mucin 21-knockout cells, suggesting impaired acquisition of low adhesive properties. Thus, mucin 21 appears crucial for the survival of terminal respiratory unit-type lung adenocarcinoma cells under both adherent and low-adhesion conditions.