CD169-CD43 interaction is involved in erythroblastic island formation and erythroid differentiation.

CD169, a specific marker for macrophages, is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family which acts as an adhesion molecule implicated in cell-cell interaction via sialylated glycoconjugates. Although CD169+ macrophages have been found to participate in erythroblastic island (EBI) formation and support erythropoiesis under homeostasis and stress, the exact role of CD169 and its counter receptor in EBI remains unknown. Herein, we generated CD169-CreERT knock-in mice and investigated the function of CD169 in EBI formation and erythropoiesis using CD169-null mice. EBI formation was impaired in vitro by both blockade of CD169 using anti-CD169 antibody and deletion of CD169 on macrophages. Furthermore, CD43 expressed by early erythroblasts (EB) was identified as the counter receptor for CD169 in mediating the EBI formation via surface plasmon resonance and imaging flow cytometry. Interestingly, CD43 was proven to be a novel indicator of erythroid differentiation due to the progressive decrease of CD43 expression as EB mature. Although CD169-null mice did not display defects in bone marrow (BM) EBI formation in vivo, CD169 deficiency impeded BM erythroid differentiation probably via CD43 under stress erythropoiesis, in concert with the role of CD169 recombinant protein in hemin-induced K562 erythroid differentiation. These findings have shed light on the role of CD169 in EBI under steady and stress erythropoiesis through binding with its counter receptor CD43, suggesting that CD169-CD43 interaction might be a promising therapeutic target for erythroid disorders.

Night shifts in interns: Effects of daytime napping on autonomic activity and cognitive function.

Objective: Night shifts have adverse cognitive outcomes that might be attenuated by daytime napping. The neurovisceral integration model suggests that resting vagally mediated heart rate variability (vmHRV) is linked with cognitive function. This study investigated the relationship between resting vmHRV and cognitive function after different nap durations in interns after shift work. Methods: A total of 105 interns were randomly allocated to one of three groups (non-nap, n = 35; 15-min nap, n = 35; 45-min nap, n = 35) to perform cognitive tests and resting vmHRV at 12:00, 15:00 and 18:00. Information processing (digit symbol substitution test; DSST), motor speed (finger tapping test; FTT), response selection (choice reaction time; CRT), and attention shifts (shifting attention test; SAT) were assessed. Resting vmHRV was assessed at baseline and during each cognitive task across groups. Results: Compared with the non-nap control, the 15-min and 45-min naps improved all outcome measures (including subjective sleepiness and cognitive performance) at 15:00, with some benefits maintained at 18:00. The 15-min nap produced significantly greater benefits on the FTT at 15:00 after napping than did the 45-min nap. Resting vmHRV was significantly correlated with DSST and SAT performance. In addition, FTT performance was the only significant predictor of DSST performance across different nap durations. Conclusion: Our results demonstrate links between daytime napping (in particular, a 15-min nap) and improved cognitive control in relation to autonomic activity after shift work in interns. These results indicated that autonomic activity when awake plays a crucial role in DSST and SAT performance and facilitated the understanding of differences in neurocognitive mechanisms underlying information processing after different nap durations.

Enhanced Homing of CXCR-4 Modified Bone Marrow-Derived Mesenchymal Stem Cells to Acute Kidney Injury Tissues by Micro-Bubble-Mediated Ultrasound Exposure.

Although the curative effects of bone marrow stromal cells (BMSCs) for acute kidney injury (AKI) have been recognized, their in vivo reparative capability is limited by the low levels of targeted homing and retention of intravenous injected cells. Stromal cell-derived factor-1 (SDF-1) plays an important role in stem cell homing and retention through interaction with its specific functional receptor, CXCR4, which is presumably related to the poor homing in AKI therapy. However, most of the functional CXCR4 chemokine receptors are lost upon in vitro culturing. Ultrasound-targeted micro-bubble destruction (UTMD) has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve BMSC homing to AKI kidneys, we isolated and cultured rat BMSCs to third passage and enhanced CXCR-4 transfection efficiency in vitro by applying UTMD and polyethylenimine. Transwell migration assay showed that the migration ability of CXCR4-modified BMSCs was nine-fold higher than controls. Then, mercuric chloride-induced AKI rats were injected with transfected BMSCs through their tail veins. We showed that enhanced homing and retention of BMSCs were observed in the CXCR-4 modified group compared with other groups at 1, 2 and 3 d post-treatment. Collectively, our data indicated that UTMD was an effective method to increase BMSCs' engraftment to AKI kidney tissues by increasing CXCR-4 expression.

Effects of diagnostic ultrasound-targeted microbubble destruction on the homing ability of bone marrow stromal cells to the kidney parenchyma.

OBJECTIVES: Bone marrow stromal cells (BMSC) transplantation proves successful in treating kidney disease and injury in many studies. However, their reparative capacity is limited by the poor homing ability in vivo, which is decided mainly by the local expression of chemoattractants. Our study explored the mechanical effects of ultrasound targeted microbubble destruction (UTMD) on BMSCs homing ability in treated kidney tissues. METHODS: Rats were injected with red fluorescent protein (RFP)-labelled BMSCs and sonicated with microbubble-mediated ultrasound. Then, we tested kidney micro-environment changes induced and their influence on stem cell homing ability. RESULTS: The results showed that the mechanical effects of UTMD would increase local and transient levels of chemoattractants (i.e. cytokines, integrins and growth factors) in targeted kidney tissues. Transmission electron microscopy showed that vascular endothelial cell was discontinuous in the UTMD group post-treatment, becoming smooth 72 h later. Confocal laser scanning microscopy and RT-PCR showed up to eight times more stem cells in the peritubular regions of experimental kidneys on days 1 and 3 post-treatment compared with the contralateral kidney. CONCLUSIONS: These results confirmed that renal micro-environment changes caused by appropriate UTMD may promote BMSC homing ability toward treated kidney tissues without renal toxicity and cell damage. KEY POINTS: • This experiment showed a feasible strategy in promoting stem cell homing ability. • The treatment uses diagnostic ultrasound during enhancement with IV microbubbles. • A suitable micro-environment was important for targeted stem cell homing and retention. • The method is effective for stem cell homing to kidney diseases. • More work is required with larger animals before potential human trials.

Enhanced Homing Ability and Retention of Bone Marrow Stromal Cells to Diabetic Nephropathy by Microbubble-Mediated Diagnostic Ultrasound Irradiation.

Bone marrow stromal cell (BMSC) transplantation can successfully treat diabetic nephropathy (DN), but the lack of a specific homing place for intravenously injected cells limits the effective implementation of stem cell therapies. The migration and survival of transplanted BMSCs are determined by inflammatory reactions in the local kidney micro-environment. We tested the hypothesis that microbubble-mediated diagnostic ultrasound irradiation could provide a suitable micro-environment for BMSC delivery and retention in DN therapy. In this study, red fluorescent protein-labeled BMSCs were administered combined with microbubbles to streptozotocin-induced DN rats 4 wk after diabetes onset. We observed enhanced BMSC homing and retention in microbubble-mediated diagnostic ultrasound-irradiated kidneys compared with the contralateral kidneys on days 1 and 3 post-treatment. The results from immunohistochemical analysis, Western blot and enzyme-linked immunosorbent assay indicated that the local and transient expression of various chemo-attractants (i.e., cytokines, integrins and trophic factors) found to promote BMSC homing was much higher than observed in non-treated kidneys. The local capillary endothelium rupture observed by transmission electron microscopy may account for local micro-environment changes. Histopathologic analysis revealed no signs of kidney damage. These results confirmed that renal micro-environment changes caused by appropriate microbubble-mediated diagnostic ultrasound irradiation may promote BMSC homing ability to the diabetic kidney without renal toxicity and cell damage. This non-invasive and effective technique may be a promising method for BMSC transplantation therapy.