Hematopoietic stem cells on the crossroad between purinergic signaling and innate immunity.

Hematopoiesis is regulated by several mediators such as peptide-based growth factors, cytokines, and chemokines, whose biological effects have been studied for many years. However, several other mediators have been identified recently that affect the fate of hematopoietic stem/progenitor cells (HSPC) as well as non-hematopoietic cells in the bone marrow microenvironment. These new mediators comprise members of purinergic signaling pathways and are active mediators of the soluble arm of innate immunity, the complement cascade (ComC). In this review, we will discuss the coordinated effects of these pathways in regulating the biology of HSPC. Importantly, both purinergic signaling and the ComC are activated in stress situations and interact with specific receptors expressed on HSPC. Evidence has accumulated indicating that some of the purinergic as well as ComC receptors could also be activated intracellularly by intrinsically expressed ligands. To support this recent evidence, our work indicates that the major mediator of purinergic signaling, adenosine triphosphate, and the cleavage product of the fifth component of the ComC (C5), C5a anaphylatoxin, can activate their corresponding receptors expressed on the outer mitochondrial membrane in an autocrine manner. We will also discuss recent evidence that these responses, mediated by purinergic signaling and the ComC network, are coordinated by activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 - reactive oxygen species - NLR family pyrin domain containing 3 (NLRP3) inflammasome (Nox2-ROS-NLRP3) axis.

The "Mystery Cell Population" Residing in Murine Bone Marrow - A Missing Link Between Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells?

Bone marrow (BM) contains not only hematopoietic stem cells (HSCs) but also some very rare, early development, small quiescent stem cells that, upon activation, may differentiate across germlines. These small cells, named very small embryonic like stem cells (VSELs), can undergo specification into several types of cells including HSCs. Interestingly, murine BM is also home to a "mystery" population of small CD45+ stem cells with many of the phenotypic characteristics attributed to resting HSCs. Since the size of the "mystery" population cells are between that of VSELs and HSCs, and because CD45- VSELs can be specified into CD45+ HSCs, we hypothesized that the quiescent CD45+ "mystery" population could be a missing developmental link between VSELs and HSCs. To support this hypothesis, we showed that VSELs first became enriched for HSCs after acquiring expression of the CD45 antigen already expressed on "mystery" stem cells. Moreover, VSELs freshly isolated from BM similar to the "mystery" population cells, are quiescent and do not reveal hematopoietic potential in in vitro and in vivo assays. However, we noticed that CD45+ "mystery" population cells, similar to CD45- VSELs, became specified into HSCs after co-culture over OP9 stroma. We also found that mRNA for Oct-4, a pluripotency marker that is highly expressed in VSELs, is also detectable in the "mystery" population cells, albeit at a much lower level. Finally, we determined that the "mystery" population cells specified over OP9 stroma support were able to engraft and establish hematopoietic chimerism in lethally irradiated recipients. Based on these results, we propose that the murine BM "mystery" population could be an intermediate population between BM-residing VSELs and HSCs already specified for lympho-hematopoietic lineages.

Detecting Primary Progressive Aphasia Atrophy Patterns: A Comparison of Visual Assessment and Quantitative Neuroimaging Techniques.

Background: There are now clinically available automated MRI analysis software programs that compare brain volumes of patients to a normative sample and provide z-score data for various brain regions. These programs have yet to be validated in primary progressive aphasia (PPA). Objective: To address this gap in the literature, we examined Neuroreader™ z-scores in PPA, relative to visual MRI assessment. We predicted that Neuroreader™ 1) would be more sensitive for detecting left > right atrophy in the cortical lobar regions in logopenic variant PPA clinical phenotype (lvPPA), and 2) would distinguish lvPPA (n = 11) from amnestic mild cognitive impairment (aMCI; n = 12). Methods: lvPPA or aMCI patients who underwent MRI with Neuroreader™ were included in this study. Two neuroradiologists rated 10 regions. Neuroreader™ lobar z-scores for those 10 regions, as well as a hippocampal asymmetry metric, were included in analyses. Results: Cohen's Kappa coefficients were significant in 10 of the 28 computations (k = 0.351 to 0.593, p≤0.029). Neuroradiologists agreed 0% of the time that left asymmetry was present across regions. No significant differences emerged between aMCI and lvPPA in Neuroreader™ z-scores across left or right frontal, temporal, or parietal regions (ps > 0.10). There were significantly lower z-scores in the left compared to right for the hippocampus, as well as parietal, occipital, and temporal cortices in lvPPA. Conclusion: Overall, our results indicated moderate to low interrater reliability, and raters never agreed that left asymmetry was present. While lower z-scores in the left hemisphere regions emerged in lvPPA, Neuroreader™ failed to differentiate lvPPA from aMCI.