Biology subjects

Shim, J.-H.

Publications and source records attributed to Shim, J.-H..

4 recordsLinked to original sources

bioRxiv2024

Neuron-derived Prox1 suppresses injury-induced reprogramming of Muller glia to proliferative retinal progenitor cells

Individuals with retinal degenerative diseases face significant obstacles in restoring normal vision due to the inability to regenerate degenerated retinal cells. While retinal neurons can be regenerated from Muller glia (MG) in cold-blooded vertebrates, this regenerative ability is lacking in mammals, indicating the limited competence of mammalian MG for retinal regeneration. In this study, we elucidate the role of prospero-related homeobox 1 (Prox1) in rendering the mammalian retina incompetent for MG-derived regeneration. Prox1 accumulates in MG in the degenerating human and mouse retinas but not in those in the regenerating zebrafish retina. Strikingly, Prox1 in mouse MG originated from neighboring retinal neurons through intercellular protein transfer. Consequently, inhibition of Prox1 transfer to MG enables the reprogramming of MG into proliferative retinal progenitor cells in injured mouse retinas. Furthermore, we succeeded in regenerating retinal neurons and delaying vision loss in retinitis pigmentosa disease model in mice by adenoassociated viral gene delivery of an anti-Prox1 antibody that sequesters extracellular Prox1 in the mouse retina. Taken together, our findings highlight the therapeutic potential of anti-Prox1 therapy in restoring the regenerative potential of the mammalian retina.

developmental biology↗

bioRxiv2024

Nucleic Acid Aptamers Protect Against Lead (Pb(II)) Toxicity

Lead (Pb(II)) is a pervasive heavy metal toxin with many well-established negative effects on human health. Lead toxicity arises from cumulative, repeated environmental exposures. Thus, prophylactic strategies to protect against the bioaccumulation of lead could reduce lead-associated human pathologies. Here we show that DNA and RNA aptamers protect C. elegans from toxic phenotypes caused by lead. Reproductive toxicity, as measured by brood size assays, is prevented by co-feeding of animals with DNA or RNA aptamers. Similarly, lead-induced behavioral anomalies are also normalized by aptamer feeding. Further, cultured human HEK293 and primary murine osteoblasts are protected from lead toxicity by transfection with DNA aptamers. The osteogenic development, which is decreased by lead exposure, is maintained by prior transfection of lead-binding DNA aptamers. Aptamers may be an effective strategy for the protection of human health in the face of increasing environmental toxicants. SYNOPSISLead remains a pervasive environmental contaminant with significant human health implications. This study investigates an entirely novel intervention for the problem of lead toxicity, using nucleic acid aptamers.

pharmacology and toxicology↗

bioRxiv2022

Impaired ERK MAPK activation in mature osteoblasts enhances bone formation via the mTOR pathway

Emerging evidence supports that osteogenic differentiation of skeletal stem cells (SSCs) is a key determinant of overall bone formation and bone mass. Despite extensive studies showing mitogen-activated protein kinase (MAPK) function in osteoblast differentiation, none of these studies properly show in vivo evidence of impacting post-lineage commitment and subsequent maturation. Here, we describe how the extracellular signal-regulated kinase (ERK) pathway in osteoblasts controls bone formation by suppressing the mechanistic target of rapamycin (mTOR) pathway. We also show that, while ERK inhibition blocks the differentiation of osteogenic precursors when initiated at an early stage, ERK inhibition surprisingly promotes the later stages of osteoblast differentiation. Accordingly, inhibition of the ERK pathway using a small compound inhibitor or conditional deletion of the MAP2Ks Mek1 and Mek2, in mature osteoblasts and osteocytes (Mek1/2Dmp1), markedly increased bone formation due to augmented osteoblast differentiation. Mice with inducible deletion of the ERK pathway in mature osteoblasts (Mek1/2Ocn-Ert) also displayed similar phenotypes, demonstrating that this phenotype reflects continuous postnatal inhibition of late-stage osteoblast maturation. Mechanistically, ERK inhibition increases mitochondrial function and SGK1 phosphorylation via mTOR2 activation, which leads to osteoblast differentiation and production of angiogenic and osteogenic factors to promote bone formation. This phenotype was partly reversed by inhibiting mTOR. Our study uncovers a surprising dichotomy of ERK pathway functions in osteoblasts, whereby ERK activation promotes the early differentiation of osteoblast precursors, but inhibits the subsequent differentiation of committed osteoblasts via mTOR-mediated regulation of mitochondrial function and SGK1.

molecular biology↗

bioRxiv2020

The ESCRT protein CHMP5 restrains skeletal progenitor cell senescence by preserving endo-lysosomal-mitochondrial network

The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.

cell biology↗