SUMMARY The scarcity of tissue-specific stem cells and the complexity of their surrounding environment have made molecular characterization of these cells particularly challenging. Through single-cell transcriptome and weighted gene co-expression network analysis (WGCNA), we uncovered molecular properties of CD133+/GFAP− ependymal (E) cells in the adult mouse forebrain neurogenic zone. Surprisingly, prominent hub genes of the gene network unique to ependymal CD133+/GFAP− quiescent cells were enriched for immune-responsive genes, as well as genes encoding receptors for angiogenic factors. Administration of vascular endothelial growth factor (VEGF) activated CD133+ ependymal neural stem cells (NSCs), lining not only the lateral but also the fourth ventricles and, together with basic fibroblast growth factor (bFGF), elicited subsequent neural lineage differentiation and migration. This study revealed the existence of dormant ependymal NSCs throughout the ventricular surface of the CNS, as well as signals abundant after injury for their activation.

Electrical impedance myography (EIM) is a non-invasive, painless technique for the evaluation of neuromuscular disease, and here we evaluate its potential application in spinal muscular atrophy (SMA). Twenty-one SMA patients and 18 healthy children underwent EIM of biceps brachii and tibialis anterior using a commercially available impedance device. Hand-held dynamometry and ultrasound assessment of subcutaneous fat thickness were also performed. All EIM parameters differed significantly between both SMA patients and normal subjects and between type 2 and type 3 SMA patients. In addition, EIM had an accuracy level as high as 93% for correctly categorizing patients as type 2 or type 3. Multiple regression analyses confirmed a strong association between EIM and dynamometry. These results confirm that EIM can accurately categorize patients with SMA. Because EIM requires no patient effort and is rapid to apply, it may serve a useful role in future SMA clinical trials.

Inhibition of angiotensin-converting enzyme (ACE) induces anemia in humans and mice, but it is unclear whether ACE is involved in other aspects of hematopoiesis. Here, we systemically evaluated ACE-knockout (KO) mice and found myelopoietic abnormalities characterized by increased bone marrow myeloblasts and myelocytes, as well as extramedullary myelopoiesis. Peritoneal macrophages from ACE-KO mice were deficient in the production of effector molecules, such as tumor necrosis factor-α, interleukin-12p40, and CD86 when stimulated with lipopolysaccharide and interferon-γ. ACE-KO mice were more susceptible to Staphylococcus aureus infection. Further studies using total or fractionated bone marrows revealed that ACE regulates myeloid proliferation, differentiation, and functional maturation via angiotensin II and substance P and through the angiotensin II receptor type 1 and substance P neurokinin 1 receptors. Angiotensin II was correlated with CCAAT-enhancer-binding protein-α up-regulation during myelopoiesis. Angiotensin II supplementation of ACE-KO mice rescued macrophage functional maturation. These results demonstrate a previous unrecognized significant role for ACE in myelopoiesis and imply new perspectives for manipulating myeloid cell expansion and maturation.

The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to CD8+ T cell mediated adaptive immune responses. Aminopeptidases are implicated in the editing of peptides for MHC class I loading, but C-terminal editing is thought due to proteasome cleavage. By comparing genetically deficient, wild-type and over-expressing mice, we now identify the dipeptidase angiotensin-converting enzyme (ACE) as playing a physiologic role in peptide processing for MHC class I. ACE edits the C-termini of proteasome-produced class I peptides. The lack of ACE exposes novel antigens but also abrogates some self-antigens. ACE has major effects on surface MHC class I expression in a haplotype-dependent manner. We propose a revised model of MHC class I peptide processing by introducing carboxypeptidase activity.