Significance Statement: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment observed in patients with CKD. Some uremic toxins, such as indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR). The authors found that cognitive impairment in three models of CKD in rats is correlated with serum levels of indoxyl sulfate as well as blood-brain barrier disruption as detected by SPECT/CT imaging. Using AhR^−/− knockout mice, the authors described for the first time that indoxyl sulfate–induced activation of AhR is responsible for blood-brain barrier disruption. These findings demonstrate that blood-brain barrier disruption seems to be an important mechanism involved in cognitive impairment in the context of CKD and that AhR may be a promising therapeutic target to prevent cognitive impairment in CKD. Background: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells. Methods: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR^−/− knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of ^99mTc-DTPA, an imaging marker of blood-brain barrier permeability. Results: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between ^99mTc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR^−/− knockout mice were protected against indoxyl sulfate–induced blood-brain barrier disruption and cognitive impairment. Conclusions: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

Significance: Nanotechnology-based imaging is expected to bring breakthroughs in cancer diagnosis by improving imaging sensitivity and specificity while reducing toxicity. Here, we developed an innovative nanosystem for positron emission tomography (PET) imaging based on a self-assembling amphiphilic dendrimer. This dendrimer assembled spontaneously into uniform supramolecular nanomicelles with abundant PET reporting units on the surface. By harnessing both dendrimeric multivalence and the “enhanced permeation and retention” (EPR) effect, this dendrimer nanosystem effectively accumulated in tumors, leading to exceedingly sensitive and specific imaging of various tumors, especially those that are otherwise undetectable using the clinical gold reference 2-fluorodeoxyglucose ([ ¹⁸ F]FDG). This study illustrates the power of nanotechnology based on self-assembling dendrimers to provide an effective platform for bioimaging and related biomedical applications.

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the ¹⁸F chemical toolbox gave aluminum [¹⁸F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [¹⁸F][AlF]²⁺ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [¹⁸F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [¹⁸F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [¹⁸F]AlF labeling applications through a description of the various [¹⁸F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.

Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism. We investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo . In a mouse model of hindlimb ischaemia, the homing of radiolabelled cells to ischaemic tissue was assessed by SPECT-CT imaging. Soluble CD146 priming did not modify the number of engrafted ECFC but improved their survival capacity, leading to an enhanced revascularization. The mechanism of action of sCD146 on ECFC was studied in vitro. We showed that sCD146 acts in ECFC through a signalosome, located in lipid rafts, containing angiomotin, the short isoform of CD146 (shCD146), VEGFR1, VEGFR2, and presenilin-1. Soluble CD146 induced a sequential proteolytic cleavage of shCD146, with an extracellular shedding followed by an intramembrane cleavage mediated by matrix metalloprotease (MMP)/ADAM and presenilin-1, respectively. The generated intracellular part of shCD146 was directed towards the nucleus where it associated with the transcription factor CSL and modulated the transcription of genes involved in cell survival ( FADD , Bcl-xl ) and angiogenesis ( eNOS ). This effect was dependent on both VEGFR1 and VEGFR2, which were rapidly phosphorylated by sCD146. These findings establish that activation of the proteolytic processing of shCD146, in particular by sCD146, constitutes a promising pathway to improve endothelial progenitors' regenerative properties for the treatment of cardiovascular diseases.

Neonatal hypoxic-ischemic encephalopathy (NHIE) is a dramatic perinatal complication, associated with poor neurological prognosis despite neuroprotection by therapeutic hypothermia, in the absence of an available curative therapy. We evaluated and compared ready-to-use human umbilical cord blood cells (HUCBC) and bankable but allogeneic endothelial progenitors (ECFC) as cell therapy candidate for NHIE. We compared benefits of HUCBC and ECFC transplantation 48 hours after injury in male rat NHIE model, based on the Rice-Vannucci approach. Based on behavioral tests, immune-histological assessment and metabolic imaging of brain perfusion using single photon emission computed tomography (SPECT), HUCBC, or ECFC administration provided equally early and sustained functional benefits, up to 8 weeks after injury. These results were associated with total normalization of injured hemisphere cerebral blood flow assessed by SPECT/CT imaging. In conclusion, even if ECFC represent an efficient candidate, HUCBC autologous criteria and easier availability make them the ideal candidate for hypoxic-ischemic cell therapy. Stem Cells Translational Medicine 2017;6:1987–1996