Decreased Tiam1-mediated Rac1 activation is responsible for impaired directional persistence of chondrocyte migration in microtia.

The human auricle has a complex structure, and microtia is a congenital malformation characterized by decreased size and loss of elaborate structure in the affected ear with a high incidence. Our previous studies suggest that inadequate cell migration is the primary cytological basis for the pathogenesis of microtia, however, the underlying mechanism is unclear. Here, we further demonstrate that microtia chondrocytes show a decreased directional persistence during cell migration. Directional persistence can define a leading edge associated with oriented movement, and any mistakes would affect cell function and tissue morphology. By the screening of motility-related genes and subsequent confirmations, active Rac1 (Rac1-GTP) is identified to be critical for the impaired directional persistence of microtia chondrocytes migration. Moreover, Rho guanine nucleotide exchange factors (GEFs) and Rho GTPase-activating proteins (GAPs) are detected, and overexpression of Tiam1 significantly upregulates the level of Rac1-GTP and improves directional migration in microtia chondrocytes. Consistently, decreased expression patterns of Tiam1 and active Rac1 are found in microtia mouse models, Bmp5se/J and Prkralear-3J/GrsrJ. Collectively, our results provide new insights into microtia development and therapeutic strategies of tissue engineering for microtia patients.

Developmentally regulated expression of integrin alpha-6 distinguishes neural crest derivatives in the skin.

Neural crest-derived cells play essential roles in skin function and homeostasis. However, how they interact with environmental cues and differentiate into functional skin cells remains unclear. Using a combination of single-cell data analysis, neural crest lineage tracing, and flow cytometry, we found that the expression of integrin α6 (ITGA6) in neural crest and its derivatives was developmentally regulated and that ITGA6 could serve as a functional surface marker for distinguishing neural crest derivatives in the skin. Based on the expression of ITGA6, Wnt1-Cre lineage neural crest derivatives in the skin could be categorized into three subpopulations, namely, ITGA6bright, ITGA6dim, and ITGA6neg, which were found to be Schwann cells, melanocytes, and fibroblasts, respectively. We further analyzed the signature genes and transcription factors that specifically enriched in each cell subpopulation, as well as the ligand or receptor molecules, mediating the potential interaction with other cells of the skin. Additionally, we found that Hmx1 and Lhx8 are specifically expressed in neural crest-derived fibroblasts, while Zic1 and homeobox family genes are expressed in mesoderm-derived fibroblasts, indicating the distinct development pathways of fibroblasts of different origins. Our study provides insights into the regulatory landscape of neural crest cell development and identifies potential markers that facilitate the isolation of different neural crest derivatives in the skin.

NOVA1 prevents overactivation of the unfolded protein response and facilitates chromatin access during human white adipogenesis.

The molecular mechanism underlying white adipogenesis in humans has not been fully elucidated beyond the transcriptional level. Here, we found that the RNA-binding protein NOVA1 is required for the adipogenic differentiation of human mesenchymal stem cells. By thoroughly exploring the interactions between NOVA1 and its binding RNA, we proved that NOVA1 deficiency resulted in the aberrant splicing of DNAJC10 with an in-frame premature stop codon, reduced DNAJC10 expression at the protein level and hyperactivation of the unfolded protein response (UPR). Moreover, NOVA1 knockdown abrogated the down-regulation of NCOR2 during adipogenesis and up-regulated the 47b+ splicing isoform, which led to decreased chromatin accessibility at the loci of lipid metabolism genes. Interestingly, these effects on human adipogenesis could not be recapitulated in mice. Further analysis of multispecies genomes and transcriptomes indicated that NOVA1-targeted RNA splicing is evolutionarily regulated. Our findings provide evidence for human-specific roles of NOVA1 in coordinating splicing and cell organelle functions during white adipogenesis.

Intraneural hemangioma of spinal nerve roots: a Case Report and literature review.

Intraneural hemangiomas are rare benign neoplasms. We report the case of a 53­year­old female with a hemangioma in a spinal nerve root. The patient presented with muscular atropy of the right arm wihout obvious predisposing factors one year ago. MRI demonstrated a heterogeneously enhanced lesion adjacent to the right C4/5 intervertebral foramen. The lesion was considered to be a schwannoma preoperatively. Histologically, the lesion was abundant with intervening malformed vascular mass lined by simple squamous epithelial cells, and CD31 was positively stained at these epithelial cells by immunohistochemistry. The patient underwent microsurgical resection and recovered without complications.

The relationship between the apparent diffusion coefficient and the Ki-67 proliferation index in intracranial solitary fibrous tumor/hemangiopericytoma.

This study evaluated the value of the apparent diffusion coefficient (ADC) in distinguishing grade II and III intracranial solitary fibrous tumors/hemangiopericytomas and explored the correlation between ADC and Ki-67. The preoperative MRIs of 37 patients treated for solitary fibrous tumor/hemangiopericytoma (grade II, n = 15 and grade III, n = 22) in our hospital from 2011 to October 2020 were retrospectively analyzed. We compared the difference between the minimum, average, maximum, and relative ADCs based on tumor grade and examined the correlation between ADC and Ki-67. Receiver operating characteristic curve analysis was used to analyze the diagnostic efficiency of the ADC. There were significant differences in the average, minimum, and relative ADCs between grade II and III patients. The optimal cutoff value for the relative ADC value to differentiate grade II and III tumors was 0.998, which yielded an area under the curve of 0.879. The Ki-67 proliferation indexes of grade II and III tumors were significantly different, and the average (r = - 0.427), minimum (r = - 0.356), and relative (r = - 0.529) ADCs were significantly negatively correlated with the Ki-67 proliferation index. ADC can be used to differentiate grade II and III intracranial solitary fibrous tumors/hemangiopericytomas. Our results can be used to formulate a personalized surgical treatment plan before surgery.

OLFML2A Downregulation Inhibits Glioma Proliferation Through Suppression of Wnt/ß-Catenin Signaling.

Glioma is a highly heterogeneous and lethal tumor with an extremely poor prognosis. Through analysis of TCGA data, we identified that OLFML2A is a key promotor of gliomagenesis. However, the molecular function of OLFML2A and its underlying mechanism of action in glioma remain unclear. In this study, we found that OLFML2A expression was significantly upregulated in glioma specimens and positively correlated with pathological grades in glioma patients. Moreover, Kaplan-Meier survival analysis of TCGA data revealed that glioma patients with higher OLFML2A expression had shorter overall survival. Importantly, OLFML2A knockdown in glioma cells inhibited cell proliferation and promoted apoptosis. Mechanistically, OLFML2A downregulation inhibits Wnt/ß-catenin signaling by upregulating amyloid precursor protein (APP) expression and reducing stabilized ß-catenin levels, leading to the repression of MYC, CD44, and CSKN2A2 expression. Furthermore, OLFML2A downregulation suppressed the growth of transplanted glioma subcutaneously and intracranially by inhibiting Wnt/ß-catenin pathway-dependent cell proliferation. By uncovering the oncogenic effects in human and rodent gliomas, our data support OLFML2A as a potential therapeutic target for glioma.

CD49fhigh Defines a Distinct Skin Mesenchymal Stem Cell Population Capable of Hair Follicle Epithelial Cell Maintenance.

The dermis harbors distinct mesenchymal stem cell (MSC) populations, which play equally important roles as epidermal stem cells in skin homeostasis and regeneration. However, to reliably identify and directly isolate the in vivo counterpart of these cells is still challenging. Using the epidermal stem cell marker CD49f, we defined a CD49fhigh distinct mesenchymal subpopulation in the dermis. In vitro and in vivo differentiation assays, and transcriptome analysis demonstrated that CD49fhigh cells possess neural crest-like cell characteristics. Our results showed that the formation of hair follicle-like budding structure and the expressions of key genes regulating hair follicle development were induced when hair follicle epithelial cells were co-cultured with CD49fhigh cells. We also found that CD49fhigh cells activated Notch signaling in co-cultured hair follicle epithelial cells, whereas the inhibition of Notch signaling resulted in epidermal cyst-like spheres and loss of maintenance of hair follicle epithelial cell characteristics. Furthermore, we identified Itga7 and CD49f as an efficient biomarker panel for direct selection of CD49fhigh skin MSCs. Our results lead to a deeper understanding of heterogeneity and the function of MSCs in the skin and may facilitate potential translational applications of these cells.

Human Umbilical Cord-Derived Mesenchymal Stromal Cells Improve Left Ventricular Function, Perfusion, and Remodeling in a Porcine Model of Chronic Myocardial Ischemia.

UNLABELLED: : Stem cell therapy has emerged as a new strategy for treatment of ischemic heart disease. Although umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have been used preferentially in the acute ischemia model, data for the chronic ischemia model are lacking. In this study, we investigated the effect of UC-MSCs originated from Wharton's jelly in the treatment of chronic myocardial ischemia in a porcine model induced by ameroid constrictor. Four weeks after ameroid constrictor placement, the surviving animals were divided randomly into two groups to undergo saline injection (n = 6) or UC-MSC transplantation (n = 6) through the left main coronary artery. Two additional intravenous administrations of UC-MSCs were performed in the following 2 weeks to enhance therapeutic effect. Cardiac function and perfusion were examined just before and at 4 weeks after intracoronary transplantation. The results showed that pigs with UC-MSC transplantation exhibited significantly greater left ventricular ejection fraction compared with control animals (61.3% ± 1.3% vs. 50.3% ± 2.0%, p < .05). The systolic thickening fraction in the infarcted left ventricular wall was also improved (41.2% ± 3.3% vs. 46.2% ± 2.3%, p < .01). Additionally, the administration of UC-MSCs promoted collateral development and myocardial perfusion. The indices of fibrosis and apoptosis were also significantly reduced. Immunofluorescence staining showed clusters of CM-DiI-labeled cells in the border zone, some of which expressed von Willebrand factor. These results suggest that UC-MSC treatment improves left ventricular function, perfusion, and remodeling in a porcine model with chronic myocardial ischemia. SIGNIFICANCE: Ischemic heart disease is the leading cause of death worldwide. Many patients with chronic myocardial ischemia are not suitable for surgery and have no effective drug treatment; they are called "no-option" patients. This study finds that umbilical cord-derived mesenchymal stromal cells transplanted by intracoronary delivery combined with two intravenous administrations was safe and could significantly improve left ventricular function, perfusion, and remodeling in a large-animal model of chronic myocardial ischemia, which provides a new choice for the no-option patients. In addition, this study used clinical-grade mesenchymal stem cells with delivery and assessment methods commonly used clinically to facilitate further clinical transformation.

CD49f Acts as an Inflammation Sensor to Regulate Differentiation, Adhesion, and Migration of Human Mesenchymal Stem Cells.

The advent of mesenchymal stem cell (MSC)-based therapies has been an exciting innovation for the treatment of degenerative and inflammatory diseases. However, the surface markers that accurately reflect the self-renewal and differentiation potential of MSCs and their sensitivity to environmental cues remain poorly defined. Here, we studied the role of CD49f in bone marrow MSCs (BMSCs) and the mechanism by which it regulates the behavior of BMSCs under inflammatory conditions. We found that CD49f is preferentially expressed in fetal cells rather than adult cells, CD49f-positive BMSCs possess higher CFU-F formation ability and differentiation potential than CD49f negative cells, and the CD49f expression of BMSCs gradually decreases during in vitro passaging. CD49f knockdown dramatically decreased the differentiation of BMSCs and isoform A was demonstrated to be the main functional form that enhanced the differentiation ability of BMSCs. The influences of inflammatory cytokines on BMSCs revealed that TNF-α downregulated CD49f in BMSCs with impaired differentiation, decreased adhesion to laminins, and increased migration. Moreover, tissue transglutaminase was found to work together with CD49f to regulate the behavior of BMSCs. Finally, we showed that mTOR signaling rather than NF-κB activation mediated CD49f downregulation induced by TNF-α and maintained CD49f homeostasis in BMSCs. Our findings suggest that CD49f is a stemness marker of BMSCs and is tightly correlated with the behavioral changes of BMSCs under inflammatory conditions. These data demonstrate a novel role for CD49f in sensing inflammation through mTOR pathway to further modulate the behavior of MSCs to fulfill the requirements of the body.