6 research outputs found
Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo
A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)(neg)alpha 4 beta 7(+) precursors in the adult murine bone marrow. Expanded Lin(neg)alpha 4 beta 7(+) precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.Funding Agencies|Swedish Research Council VR grant [K2015-68X-22765-01-6]; FORMAS [2016-00830]; Wallenberg Academy Fellow (WAF) program</p
Nanodiamond–Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field
The
ability to track labeled cancer cells in vivo would allow researchers
to study their distribution, growth, and metastatic potential within
the intact organism. Magnetic resonance (MR) imaging is invaluable
for tracking cancer cells in vivo as it benefits from high spatial
resolution and the absence of ionizing radiation. However, many MR
contrast agents (CAs) required to label cells either do not significantly
accumulate in cells or are not biologically compatible for translational
studies. We have developed carbon-based nanodiamond–gadoliniumÂ(III)
aggregates (NDG) for MR imaging that demonstrated remarkable properties
for cell tracking in vivo. First, NDG had high relaxivity independent
of field strength, a finding unprecedented for gadoliniumÂ(III) [GdÂ(III)]–nanoparticle
conjugates. Second, NDG demonstrated a 300-fold increase in the cellular
delivery of GdÂ(III) compared to that of clinical GdÂ(III) chelates
without sacrificing biocompatibility. Further, we were able to monitor
the tumor growth of NDG-labeled flank tumors by <i>T</i><sub>1</sub>- and <i>T</i><sub>2</sub>-weighted MR imaging
for 26 days in vivo, longer than was reported for other MR CAs or
nuclear agents. Finally, by utilizing quantitative maps of relaxation
times, we were able to describe tumor morphology and heterogeneity
(corroborated by histological analysis), which would not be possible
with competing molecular imaging modalities
Mechanisms of Gadographene-Mediated Proton Spin Relaxation
GdÂ(III)
associated with carbon nanomaterials relaxes water proton
spins at an effectiveness that approaches or exceeds the theoretical
limit for a single bound water molecule. These GdÂ(III)-labeled materials
represent a potential breakthrough in sensitivity for GdÂ(III)-based
contrast agents used for magnetic resonance imaging (MRI). However,
their mechanism of action remains unclear. A gadographene library
encompassing GdCl<sub>3</sub>, two different GdÂ(III) complexes, graphene
oxide (GO), and graphene suspended by two different surfactants and
subjected to varying degrees of sonication was prepared and characterized
for their relaxometric properties. Gadographene was found to perform
comparably to other GdÂ(III)–carbon nanomaterials; its longitudinal
(<i>r</i><sub>1</sub>) and transverse (<i>r</i><sub>2</sub>) relaxivity are modulated between 12–85 mM<sup>–1</sup> s<sup>–1</sup> and 24–115 mM<sup>–1</sup> s<sup>–1</sup>, respectively, depending on the GdÂ(III)–carbon
backbone combination. The unusually large relaxivity and its variance
can be understood under the modified Florence model incorporating
the Lipari–Szabo approach. Changes in hydration number (<i>q</i>), water residence time (τ<sub>M</sub>), molecular
tumbling rate (Ď„<sub>R</sub>), and local motion (Ď„<sub>fast</sub>) sufficiently explain most of the measured relaxivities.
Furthermore, results implicated the coupling between graphene and
GdÂ(III) as a minor contributor to proton spin relaxation