Cholesterol-binding protein TSPO2 coordinates maturation and proliferation of terminally differentiating erythroblasts
JOURNAL OF BIOLOGICAL CHEMISTRY
Authors: Kiatpakdee, Benjaporn; Sato, Kota; Otsuka, Yayoi; Arashiki, Nobuto; Chen, Yuqi; Tsumita, Takuya; Otsu, Wataru; Yamamoto, Akito; Kawata, Reo; Yamazaki, Jumpei; Sugimoto, Yoshikazu; Takada, Kensuke; Mohandas, Narla; Inaba, Mutsumi
Abstract
TSPO2 (translocator protein 2) is a transmembrane protein specifically expressed in late erythroblasts and has been postulated to mediate intracellular redistribution of cholesterol. We identified TSPO2 as the causative gene for the HK (high-K+) trait with immature red cell phenotypes in dogs and investigated the effects of the TSPO2 defects on erythropoiesis in HK dogs with the TSPO2 mutation and Tspo2 knockout (Tspo2(?/?)) mouse models. Bone marrow?derived erythroblasts from HK dogs showed increased binucleated and apoptotic cells at various stages of maturation and shed large nuclei with incomplete condensation when cultured in the presence of erythropoietin, indicating impaired maturation and cytokinesis. The canine TSPO2 induces cholesterol accumulation in the endoplasmic reticulum and could thereby regulate cholesterol availability by changing intracellular cholesterol distribution in erythroblasts. Tspo2(?/?) mice consistently showed impaired cytokinesis with increased binucleated erythroblasts, resulting in compensated anemia, and their red cell membranes had increased Na,K-ATPase, resembling the HK phenotype in dogs. Tspo2-deficient mouse embryonic stem cell?derived erythroid progenitor (MEDEP) cells exhibited similar morphological defects associated with a cell-cycle arrest at the G(2)/M phase, resulting in decreased cell proliferation and had a depletion in intracellular unesterified and esterified cholesterol. When the terminal maturation was induced, Tspo2(?/?) MEDEP cells showed delays in hemoglobinization; maturation-associated phenotypic changes in CD44, CD71, and TER119 expression; and cell-cycle progression. Taken together, these findings imply that TSPO2 is essential for coordination of maturation and proliferation of erythroblasts during normal erythropoiesis.
Self-Reporting Gold Nanourchins for Tumor-Targeted Chemo-Photothermal Therapy Integrated with Multimodal Imaging
ADVANCED THERAPEUTICS
Authors: Zhang, Beilu; Wang, Jinping; Sun, Jingyu; Wang, Yuhao; Chou, Tsengming; Zhang, Qiang; Shah, Harshal R.; Ren, Lei; Wang, Hongjun
Abstract
In search of facile yet efficient therapeutic and imaging nanoagents for cancer treatment, versatile self-reporting gold nanourchins (AuNUs) featuring synergic chemo-photothermal therapies and multimodal imaging are fabricated. AuNUs are synthesized using a surfactant-free approach, and then functionalized with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) and dopamine to form adenosine triphosphate (ATP)-cleavable boronate ester bonds prior to further immobilization with hyaluronic acid (HA) for cancer targeting. Controlled release of an anticancer drug, doxorubicin (DOX), loaded in the interstices of AuNUs, is achieved upon exposure to the overproduced hyaluronidase (HAase) in a tumor microenvironment. The spiny exterior of AuNUs enables their optophysical conversion of near-infrared (NIR) light (808 nm) to heat for photothermal therapy and IR imaging. The surface enhanced Raman scattering (SERS) of AuNUs also allows sensitive and reliable Raman mapping of their cellular uptake in vitro, and intratumoral accumulation in vivo, complementary to conventional photoacoustic imaging (PAI). With a demonstrated ability to eradicate tumors and enable multimodal imaging, AuNUs exemplify ongoing efforts in design and utility of multifunctional nanoplatforms.