Rapid induction and long-term self-renewal of neural crest-derived ectodermal chondrogenic cells from hPSCs.

Articular cartilage is highly specific and has limited capacity for regeneration if damaged. Human pluripotent stem cells (hPSCs) have the potential to generate any cell type in the body. Here, we report the dual-phase induction of ectodermal chondrogenic cells (ECCs) from hPSCs through the neural crest (NC). ECCs were able to self-renew long-term (over numerous passages) in a cocktail of growth factors and small molecules. The cells stably expressed cranial neural crest-derived mandibular condylar cartilage markers, such as MSX1, FOXC1 and FOXC2. Compared with chondroprogenitors from iPSCs via the paraxial mesoderm, ECCs had single-cell transcriptome profiles similar to condylar chondrocytes. After the removal of the cocktail sustaining self-renewal, the cells stopped proliferating and differentiated into a homogenous chondrocyte population. Remarkably, after transplantation, this cell lineage was able to form cartilage-like structures resembling mandibular condylar cartilage in vivo. This finding provides a framework to generate self-renewing cranial chondrogenic progenitors, which could be useful for developing cell-based therapy for cranial cartilage injury.

Chemical approach to generating long-term self-renewing pMN progenitors from human embryonic stem cells.

Spinal cord impairment involving motor neuron degeneration and demyelination can cause lifelong disabilities, but effective clinical interventions for restoring neurological functions have yet to be developed. In early spinal cord development, neural progenitors of the motor neuron (pMN) domain, defined by the expression of oligodendrocyte transcription factor 2 (OLIG2), in the ventral spinal cord first generate motor neurons and then switch the fate to produce myelin-forming oligodendrocytes. Given their differentiation potential, pMN progenitors could be a valuable cell source for cell therapy in relevant neurological conditions such as spinal cord injury. However, fast generation and expansion of pMN progenitors in vitro while conserving their differentiation potential has so far been technically challenging. In this study, based on chemical screening, we have developed a new recipe for efficient induction of pMN progenitors from human embryonic stem cells. More importantly, these OLIG2+ pMN progenitors can be stably maintained for multiple passages without losing their ability to produce spinal motor neurons and oligodendrocytes rapidly. Our results suggest that these self-renewing pMN progenitors could potentially be useful as a renewable source of cell transplants for spinal cord injury and demyelinating disorders.

Coaxial Electrospun PLLA Fibers Modified with Water-Soluble Materials for Oligodendrocyte Myelination.

Myelin sheaths are essential in maintaining the integrity of axons. Development of the platform for in vitro myelination would be especially useful for demyelinating disease modeling and drug screening. In this study, a fiber scaffold with a core-shell structure was prepared in one step by the coaxial electrospinning method. A high-molecular-weight polymer poly-L-lactic acid (PLLA) was used as the core, while the shell was a natural polymer material such as hyaluronic acid (HA), sodium alginate (SA), or chitosan (CS). The morphology, differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), contact angle, viability assay, and in vitro myelination by oligodendrocytes were characterized. The results showed that such fibers are bead-free and continuous, with an average size from 294 ± 53 to 390 ± 54 nm. The DSC and FTIR curves indicated no changes in the phase state of coaxial brackets. Hyaluronic acid/PLLA coaxial fibers had the minimum contact angle (53.1° ± 0.24°). Myelin sheaths were wrapped around a coaxial electrospun scaffold modified with water-soluble materials after a 14-day incubation. All results suggest that such a scaffold prepared by coaxial electrospinning potentially provides a novel platform for oligodendrocyte myelination.

Does arthroscopic repair show superiority over open repair of lateral ankle ligament for chronic lateral ankle instability: a systematic review and meta-analysis.

BACKGROUND: There is still no definite consensus on whether arthroscopic repair shows superiority over open repair for chronic lateral ankle instability. We conducted a systematic review and meta-analysis of the current comparative studies to make a generalized analysis. METHODS: PubMed, Embase, and Web of Science databases were searched from inception to April 2020. Included studies were assessed by the level of evidence and quality of evidence (Cochrane Handbook or MINORS). The process of data extraction was conducted by two independent authors. The comparative results of clinical outcomes, stress radiographic outcomes, and complication rates between two groups were pooled. Statistical analysis was performed using STATA. RESULTS: Nine comparative studies for a total of 473 patients (250 arthroscopic repair, 223 open repair) were included. For the clinical outcomes, a significant difference was found in favor of arthroscopic repair with regard to AOFAS scores (MD 0.32, 95% CI 0.12 to 0.53, I2 = 7.7%, P = .370) and VAS scores (MD - 0.30, 95% CI - 0.54 to - 0.05, I2 = 48.3%, P = .102). No significant difference was found regarding to stress radiographic outcomes. Importantly, the total complication rate (RR 0.88, 95% CI 0.51 to 1.49, I2 = 0%, P = .957) as well as nerve complication rate (RR 1.21, 95% CI 0.53 to 2.75, I2 = 0%, P = .975) of arthroscopic repair group is not significantly different to that of open repair group. CONCLUSIONS: Arthroscopic repair for lateral ankle instability shows excellent clinical results comparable to open repair. Especially, arthroscopic repair might alleviate more pain due to the minimally invasive procedure. Patients receiving arthroscopic repair do not result in a higher total complication rate and nerve injury rate.

Maintenance of Primary Hepatocyte Functions In Vitro by Inhibiting Mechanical Tension-Induced YAP Activation.

Hepatocytes are the primary functional cells of the liver, performing its metabolic, detoxification, and endocrine functions. Functional hepatocytes are extremely valuable in drug discovery and evaluation, as well as in cell therapy for liver diseases. However, it has been a long-standing challenge to maintain the functions of hepatocytes in vitro. Even freshly isolated hepatocytes lose essential functions after short-term culture for reasons that are still not well understood. In the present study, we find that mechanical tension-induced yes-associated protein activation triggers hepatocyte dedifferentiation. Alleviation of mechanical tension by confining cell spreading is sufficient to inhibit hepatocyte dedifferentiation. Based on this finding, we identify a small molecular cocktail through reiterative chemical screening that can maintain hepatocyte functions over the long term and in vivo repopulation capacity by targeting actin polymerization and actomyosin contraction. Our work reveals the mechanisms underlying hepatocyte dedifferentiation and establishes feasible approaches to maintain hepatocyte functions.

Expression of DCX and Transcription Factor Profiling in Photothrombosis-Induced Focal Ischemia in Mice.

Adult neurogenesis is present in the dentate gyrus and the subventricular zone in mammalian brain under physiological conditions. Recently, adult neurogenesis has also been reported in other brain regions after brain injury. In this study, we established a focal striatal ischemic model in adult mice via photothrombosis (PT) and investigated how focal ischemia elicits neurogenesis in the striatum. We found that astrocytes and microglia increased in early post-ischemic stage, followed by a 1-week late-onset of doublecortin (DCX) expression in the striatum. The number of DCX-positive neurons reached the peak level at day 7, but they were still observed at day 28 post-ischemia. Moreover, Rbp-J (a key effector of Notch signaling) deletion in astrocytes has been reported to promote the neuron regeneration after brain ischemia, and we provided the change of gene expression profile in the striatum of astrocyte-specific Rbp-J knockout (KO) mice glial fibrillary acidic protein (GFAP-CreER:Rbp-Jfl/fl), which may help to clarify detailed potential mechanisms for the post-ischemic neurogenesis in the striatum.

Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice.

Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.