Tissue Migration Research Articles

Epilepsy in Loeys-Dietz Syndrome: The Rare Concurrence of a Connective Tissue and Neuronal Migration Disorder

We present a 7-year-old girl who presented to our emergency department in active status epilepticus. Seizures responded to standard antiepileptic medications; however, baseline work-up for seizure etiology remained unremarkable. Her new-onset seizures were further investigated via EEG and MRI brain, which revealed focal epileptiform discharges and periventricular nodular heterotopia, respectively. Concurrently, the clinical evaluation revealed extensive marfanoid features, and a personal history of eczema and asthma. Her family history was pertinent for aortic valve disease, asthma, and tall stature. Given the peculiar skeletal features, allergic propensities and coexistent weighty family history, a molecular genetic panel analysis for Marfan Syndrome and Loeys-Dietz Syndrome (LDS) were sought. Genetic testing revealed an underlying heterozygous variant in the TGFBR-1 gene; thereby confirming the presence of LDS. The child had responded well to single antiepileptic agent therapy and was discharged in good condition with regular outpatient cardiac and neurology follow-up. This is a unique case reported of a child with genetically diagnosed LDS concurring with an underlying neuronal migration disorder, manifesting in an acute, severe, and lifethreatening fashion.

Adipose tissue responds to stress-induced immunosuppression affecting immune response partially by miR-145-5p/S1PR1 pathway

Stress-induced immunosuppression (SIIS) is one of the most common problems in intensive poultry production, which can cause immunized chickens to still develop diseases and bring huge losses to production. Recently, adipose tissue, as an immunomodulatory organ, has become a hot topic of attention. However, the function and mechanism of adipose tissue involved in SIIS and its influence on the immune response are still unclear. In this study, we dynamically analyzed the correlations between the T cells migration and change of sphingosine-1-phosphate receptor 1(S1PR1) gene in adipose tissue using chicken models with different immune states, and further explored the regulatory mechanisms and application. The results showed that SIIS could significantly change the expressions of lymphocytes migration related S1PR1 gene, and SIIS could inhibit the Newcastle disease virus (NDV) immune response partially by affecting the migration and proliferation of TCRα+ T cells in adipose tissue. Moreover, the miR-145-5p/S1PR1 pathway was a potential key mechanism to regulate T cells migration in adipose tissue, and circulating miR-145-5p had potential value as a molecular marker. This research can provide innovative reference for in-depth studying the immunoregulatory function and mechanism of adipose tissue.

Cell migration within porous electrospun nanofibrous scaffolds in a mouse subcuticular implantation model.

Cellular infiltration into electrospun nanofibers (NFs) is limited due to the dense structure and small pore sizes. We developed a programmed NF collector that can fabricate porous NFs with desired pore sizes and thickness. Previously we demonstrated improved cellular proliferation and differentiation of osteoblasts, osteoclasts, and fibroblasts with increased pore sizes of polycaprolactone (PCL) NF in-vitro. This study investigated in-vivo host cell migration and vascular ingrowth within porous NF sheets implanted subcutaneously in a mouse model. Two types of PCL NFs with well-defined pore sizes were created using varying speeds of the NF collector: NF-zero (no movement, pore size 14.4 ± 8.9 µm2) and NF-high (0.232 mm/min, pore size 286.7 ± 381.9 µm2). The NF obtained by using classical flat NF collector (2D NF, pore size 1.09 ± 1.7 µm2) was a control. The three formulae of NFs were implanted subcutaneously in 18 BALB/cJ mice. Animals were killed 7 and 28-days after implantation (n = 3 per group per time point). The tissue with implanted NFs were collected for histologic analysis. Overall, 7-day samples showed little inflammatory response. At 28-days, the degree of tissue penetration of PCL NF sheet matrices was linked to pore size and area. NFs with the largest pore area had more efficient tissue migration and new blood vessel formation compared to those with smaller pore sizes. No newly formed blood vessels were observed in the 2D NF group. A porous NF scaffold with controllable pore size has potential for tissue repair/regeneration in situ with potential for many applications in orthopaedics.

Sustained acoustic medicine treatment of discogenic chronic low back pain: A randomized, multisite, double-blind, placebo-controlled trial.

Sustained acoustic medicine (SAM) is a noninvasive long-term treatment that provides essential mechanical and thermal stimulus to accelerate soft tissue healing, alleviate pain, and improve physical activity. SAM increases localized deep tissue temperature, blood flow, cellular proliferation, migration, and nutrition exchange, resulting in reduced inflammation and an increased rate of tissue regeneration. To assess the efficacy of SAM treatment of discogenic back pain in the lower spinal column to reduce pain, improve quality of life, and lower pharmacotherapy use. Sixty-five subjects with chronic low back pain were randomly assigned to SAM (N= 33) or placebo (N= 32) groups. Subjects self-applied SAM device bilaterality on the lower lumbar region for 4 hours daily for 8 weeks and completed daily pain diaries before, during, and after treatment. Subjects recorded pain reduction using a numeric rating scale (NRS), medication use, and physical activity using the Global Rating of Change (GROC) and Oswestry Disability Index (ODI). SAM treatment significantly reduced chronic lower back pain from baseline relative to placebo treatment (p< 0.0001). SAM treated subjects reported significantly lower back pain at 4 weeks, with the highest pain reduction (-2.58 points NRS, p< 0.0001) reported at 8 weeks. Similar trends were observed in improved physical activity (3.48 GROC, p< 0.0001, 69-88% ODI, p< 0.0001) and 22.5% (15.2 morphine milligram equivalent) reduction in the use of opioid medication from baseline to 8 weeks. Daily, home-use SAM treatment significantly improves the clinical symptoms of chronic lower back pain, improves physical mobility, and reduces daily medication use. SAM treatment is well-tolerated by patients and may be considered a safe, non-invasive treatment option for chronic discogenic, lower back pain.

Trimethylamine N-oxide promotes the proliferation and migration of hepatocellular carcinoma cell through the MAPK pathway

Trimethylamine-n-oxide (TMAO) is a metabolite of intestinal flora following the consumption of phosphatidylcholine-rich foods. Clinical cohort studies have shown that plasma TMAO may be a risk factor for cancer development, including hepatocellular carcinoma (HCC), but fundamental research data supporting this hypothesis are lacking. In this study, HCC cells were treated with TMAO in vivo and in vitro to evaluate the effect on some indicators related to the malignancy degree of HCC, and the relevant molecular mechanisms were explored. In vitro, TMAO promoted the proliferation and migration of HCC cells and significantly upregulated the expression of proteins related to epithelial–mesenchymal transformation (EMT). In vivo, after HCC cells were inoculated subcutaneously in nude mice given water containing TMAO, the tumors grew faster and larger than those in the mice given ordinary water. The immunohistochemistry analysis showed that proliferation, migration and EMT-related proteins in the tumor tissues were significantly upregulated by TMAO. Furthermore, TMAO obviously enhanced the phosphorylation of MAPK signaling molecules in vivo and in vitro. In conclusion, TMAO promotes the proliferation, migration and EMT of HCC cells by activating the MAPK pathway.

Abstract We012: Sheet like extracellular matrix secreting single cell microvesicles for reprogrammed endothelial cell therapy towards vascular regeneration

To enhance cell survival and engraftment for cell therapy, cell encapsulated injectable biomaterials have been widely used. However, the challenges were hypoxia and nutrient shortage in the core, inflammatory cell infiltration and limited distribution of cells from injection sites. Encapsulation of single cells in sub-100-micron microgels with higher surface to volume ratios provides more efficient oxygen and mass exchange. However, typical production of single-cell-laden microgels by microfluidics devices results in cell damage and compromised biological properties. We hypothesized that stimuli responsive amphiphilic copolymer bearing RGD peptides may self-assemble around single cells induced by cell adhesion moieties would result in single cell microvesicles (MV). A stimuli responsive amphiphilic copolymer GPM (Gelatin Poly glycerol sebacate Methacrylate) was synthesized by grafting hydrophobic synthetic polymer PGS into hydrophilic natural polymer gelatin via methacrylation followed by aza-Michael addition reaction. Single cell microvesicles of endothelial cells (EC-MVs) were fabricated by self-assembly of GPM at room temperature. For in vivo studies, sub-50-micron EC-MVs made of reprogrammed endothelial cells (rECs) were clustered into 200 micron spheres (mGPM) using sodium alginate and injected into a hindlimb ischemia model to investigate cell survival and biological function. The mGPM microspheres functioned as a barrier from immune cell infiltration and also enhanced cellular distribution. The encapsulated rECs were released over 2-4 wks in vivo and were shown robust engraftment, migration, and survival in limb tissues, promoting blood flow recovery and sustained vascular regeneration over 6 months. Interestingly, in in vitro culture, rEC-MVs secreted sheet like extra cellular matrix (ECM) which appeared to make an important role for vessel formation (neovascularization) in vivo (Figure 1). The current study clearly demonstrated the favorable biological applicability of GPM single cell MVs toward vascular regeneration by reprogrammed ECs.

Interleukin-6 and interferon-alpha differentially regulate microglia function.

Previous reports have shown that IL-6 and IFN-⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL-6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN-⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine-mediated neuroinflammatory diseases.

Epithelial CEBPD activates fibronectin and enhances macrophage adhesion in renal ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is a cause of acute kidney injury in patients after renal transplantation and leads to high morbidity and mortality. Damaged kidney resident cells release cytokines and chemokines, which rapidly recruit leukocytes. Fibronectin (FN-1) contributes to immune cell migration, adhesion and growth in inflamed tissues. CCAAT/enhancer-binding protein delta is responsive to inflammatory cytokines and stresses and plays functional roles in cell motility, extracellular matrix production and immune responses. We found that the expression of CCAAT/enhancer-binding protein delta was increased in renal epithelial cells in IRI mice compared with sham mice. Following IRI, the colocalization of FN-1 with the macrophage marker F4/80 was increased in renal injury model wild-type mice but was significantly attenuated in Cebpd-deficient mice. Inactivation of CEBPD can repress hypoxia-induced FN-1 expression in HK-2 cells. Moreover, the inactivation of CEBPD and FN-1 also reduces macrophage accumulation in HK-2 cells. These findings suggest that the involvement of CEBPD in macrophage accumulation through the activation of FN-1 expression and the inhibition of CEBPD can protect against renal IRI.

Carotid artery transplantation of brain endothelial cells enhances neuroprotection and neurorepair in ischaemic stroke rats.

Brain microvascular endothelial cells (BMECs), an important component of the neurovascular unit, can promote angiogenesis and synaptic formation in ischaemic mice after brain parenchyma transplantation. Since the therapeutic efficacy of cell-based therapies depends on the extent of transplanted cell residence in the target tissue and cell migration ability, the delivery route has become a hot research topic. In this study, we investigated the effects of carotid artery transplantation of BMECs on neuronal injury, neurorepair, and neurological dysfunction in rats after cerebral ischaemic attack. Purified passage 1 endothelial cells (P1-BMECs) were prepared from mouse brain tissue. Adult rats were subjected to transient middle cerebral artery occlusion (MCAO) for 30 min. Then, the rats were treated with 5 × 105 P1-BMECs through carotid artery infusion or tail vein injection. We observed that carotid artery transplantation of BMECs produced more potent neuroprotective effects than caudal injection in MCAO rats, including reducing infarct size and alleviating neurological deficits in behavioural tests. Carotid artery-transplanted BMECs displayed a wider distribution in the ischaemic rat brain. Immunostaining for endothelial progenitor cells and the mature endothelial cell markers CD34 and RECA-1 showed that carotid artery transplantation of BMECs significantly increased angiogenesis. Carotid artery transplantation of BMECs significantly increased the number of surviving neurons, decreased the cerebral infarction volume, and alleviated neurological deficits. In addition, we found that carotid artery transplantation of BMECs significantly enhanced ischaemia-induced hippocampal neurogenesis, as measured by doublecortin (DCX) and Ki67 double staining within 2 weeks after ischaemic injury. We conclude that carotid artery transplantation of BMECs can promote cerebral angiogenesis, neurogenesis, and neurological function recovery in adult rats after ischaemic stroke. Our results suggest that carotid injection of BMECs may be a promising new approach for treating acute brain injuries.

Unveiling the oncogenic role of LZTS1 in colorectal cancer.

Although leucine zipper tumour suppressor 1 (LZTS1) has been considered a potential tumour suppressor, accumulating evidence suggests that LZTS1 is highly expressed in many cancer types. To unravel the exact role of LZTS1 in colorectal carcinogenesis, we performed the bioinformatic analysis of LZTS1, including expression differences, correlations between expression levels and survival, methylation status of LZTS1 promoter and related cellular pathways based on TCGA dataset, GEO databases and our own CRC patient cohort. Furthermore, we confirmed the oncogenic function of LZTS1 in human mammalian cells by employing a series of assays including tissue microarray, immunoblotting, cell proliferation and migration assay. We found that the expression of LZTS1 is higher in tumour samples compared to paired normal tissue in CRC cancer and its different clinical subtypes, which is, at least in part, due to the low methylation status of LZTS1 promoter in CRC tumour samples. Functional analysis identified the close relationship between high expression of LZTS1 and PI3K-AKT pathway and the epithelial-mesenchymal transition (EMT) process. Consistently, we found that the expression of LZTS1 positively correlated with the expression PIK3CD, N-cadherin in CRC tumour samples, while the expression of LZTS1 negatively correlated with the expression of E-cadherin and PTEN in CRC tumour samples. Experimental data further confirmed that overexpression of LZTS1 upregulated activity of AKT and promoted EMT process. Furthermore, depletion of LZTS1 repressed the proliferation and migration rate of CRC cells. Thus, this study indicates that LZTS1 plays an oncogenic role in colorectal carcinogenesis.

Zigzag Barbed Polydioxanone Thread Implantation and Evaluation Using Polydimethylsiloxane Model to Simulate Thread Migration in Tissue.

Facial lifting with polydioxanone barbed threads has been widely used in aesthetic treatment for years. However, gravity resists the thread and continuously pulls the face downward. This study aims to determine methods to lift the skin more efficiently with longer longevity. The quality of the thread is important and is defined by the pulling and pullout strengths. Moreover, the method of using threads is also important. We compared five thread-implantation techniques and six angles for the V-shaped implantation methods using a polydimethylsiloxane model to simulate thread migration in tissues. The results of the simulated thread-lift techniques can provide valuable information for physicians, enabling a more precise design of facelift surgery techniques.

Tissue distribution, migration pathways and dietary risk assessment of fungicides in pomelo orchards in South China

Fungicides are used to protect vegetables and fruits from fungal diseases. Their ubiquitous utilization has resulted in water source contamination and human health concerns. However, the occurrence of fungicides in fruits and the potential implications for human health remain unclear. In this study, ninety-five fungicides were measured in pomelo and corresponding soil and leaf samples from two pomelo orchards in South China. The mean concentration of target fungicides (∑fungicides) in pulp (honey pomelo: 0.23±0.24 ng/g; shatian pomelo: 0.23±0.11 ng/g) were much lower than those in surface soil (0.53±0.57 ng/g; 1.41±1.85 ng/g) and leaf (6.97±3.20 ng/g; 28.5±11.1 ng/g). Triazole fungicides emerged as the predominant fungicides. Varied fungicides exhibit distinct tissue distribution in fruits, demonstrating diverse migration behaviors. The distribution of all fungicides followed the order: exocarp > mesocarp > endocarp > seed > pulp. No significant associations between fungicides in both soil and pulp suggest that the primary origin of fungicides in pulp may involve external exposure. Although the dietary risks of the target fungicides in pomelo were far lower than 1, it was not negligible. Our study provides novel insights into the residues and behavior of fungicides, offering foundational data for the dietary risk assessment of pomelo consumption.

Single-cell transcriptomics predicts colony stimulating factor-1 regulation of age-dependent intestinal epithelial restitution

Intestinal diseases associated with ischemic injury, which damages the principal barrier against noxious luminal contents, result in unacceptably poor outcomes in newborns. Ischemia-induced loss of the intestinal epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age-dependency of intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier versus older patients. While this age-dependence in repair has not been demonstrated in traditional rodent models, we have developed a highly translational pig model of intestinal ischemic injury and repair that does reflect this difference. We have shown that, while juvenile (weaned) pigs recover rapidly after ischemic intestinal injury, barrier repair is markedly underdeveloped in neonatal (nursing) pigs due to complete failure of epithelial restitution. Importantly, we found that restitution in neonates can be rescued by the direct application of homogenized mucosa from ischemia-injured small intestine from juvenile pigs. The mechanisms that allow for this restitution and rescue remain to be defined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells collected from recovering ischemic jejunum of juvenile pigs were processed for single cell RNA sequencing, unbiased clustering and upstream regulator analysis. A porcine intestinal epithelial cell line (IPEC-J2) and banked tissues from prior rescue experiments were qualitatively and functionally assessed for activity of predicted upstream regulators. Single cell transcriptomics in recovering juvenile epithelium revealed a subcluster of absorptive enterocytes that express several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation by many potential molecules, including colony stimulating factor-1 (CSF-1) which is known to induce cell migration in non-intestinal epithelial tissues. To begin validating this prediction, we demonstrated that CSF-1 was enriched in the ischemic juvenile mucosa which rescues neonatal restitution and documented expression of the CSF-1 receptor (CSF1R) in both neonatal and juvenile epithelium, indicating that these cells are equipped to respond to CSF-1. CSF-1 and CSF1R co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued (but not control) neonates. Further, the CSF1R inhibitor BLZ945 reduced restitution in scratch wounded IPEC-J2 cells. Single cell transcriptomics have the power to inform potential novel therapeutic targets, such as CSF-1, to improve mucosal recovery in neonates with intestinal failure in this unique and powerful pig model. NIH K01 OD028207, NIH R01 HD095876, NIH U01 TR002953, NIH T32 OD011130, NIH P30 DK034987, USDA NIFA 1007263 and 07985. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessing Bioprinted Functionalized Grafts for Biological Tendon Augmentation In Vitro.

Tendinopathy, characterized by inflammatory and degenerative changes, presents challenges in sports and medicine. In addressing the limitations of conservative management, this study focuses on developing tendon grafts using extrusion bioprinting with platelet-rich plasma (PRP)-infused hydrogels loaded with tendon cells. The objective is to understand paracrine interactions initiated by bioprinted tendon grafts in either inflamed or non-inflamed host tissues. PRP was utilized to functionalize methacrylate gelatin (GelMA), incorporating tendon cells for graft bioprinting. Bioinformatic analyses of overexpressed proteins, predictive of functional enrichment, revealed insights into PRP graft behavior in both non-inflamed and inflamed environments. PRP grafts activated inflammatory pathways, including Interleukin 17 (IL-17), neuroinflammation, Interleukin 33 (IL-33), and chemokine signaling. Interleukin 1 beta (IL-1b) in the graft environment triggered p38 mitogen-activated protein kinase (MAPK) signaling, nuclear factor kappa light chain enhancer of activated B cells (NF-kB) canonical pathway, and Vascular Endothelial Growth Factor (VEGF) signaling. Biological enrichment attributed to PRP grafts included cell chemotaxis, collagen turnover, cell migration, and angiogenesis. Acellular PRP grafts differed from nude grafts in promoting vessel length, vessel area, and junction density. Angiogenesis in cellular grafts was enhanced with newly synthesized Interleukin 8 (IL-8) in cooperation with IL-1b. In conclusion, paracrine signaling from PRP grafts, mediated by chemokine activities, influences cell migration, inflammation, and angiogenic status in host tissues. Under inflammatory conditions, newly synthesized IL-8 regulates vascularization in collaboration with PRP.

Noninvasive in vivo microscopy of single neutrophils in the mouse brain via NIR-II fluorescent nanomaterials.

In vivo microscopy of single cells enables following pathological changes in tissues, revealing signaling networks and cell interactions critical to disease progression. However, conventional intravital microscopy at visible and near-infrared wavelengths <900 nm (NIR-I) suffers from attenuation and is typically performed following the surgical creation of an imaging window. Such surgical procedures cause the alteration of the local vasculature and induce inflammation in skin, muscle and skull, inevitably altering the microenvironment in the imaging area. Here, we detail the use of near-infrared fluorescence (NIR-II, 1,000-1,700 nm) for in vivo microscopy to circumvent attenuation in living tissues. This approach enables the noninvasive visualization of cell migration in deep tissues by labeling specific cells with NIR-II lanthanide downshifting nanoparticles exhibiting high physicochemical stability and photostability. We further developed a NIR-II fluorescence microscopy setup for in vivo imaging through the intact skull with high spatiotemporal resolution, which we use for the real-time dynamic visualization of single-neutrophil behavior in the deep brain of a mouse model of ischemic stroke. The labeled downshifting nanoparticle synthesis takes 5-6 d, the imaging system setup takes 1-2 h, the in vivo cell labeling takes 1-3 h, the in vivo NIR-II microscopic imaging takes 3-5 h and the data analysis takes 3-8 h. The procedures can be performed by users with standard laboratory training in nanomaterials research and appropriate animal handling.

Phenotype and function of MAIT cells in patients with alveolar echinococcosis.

Mucosal-associated invariant T (MAIT) cells are a subpopulation of unconventional T cells widely involved in chronic liver diseases. However, the potential role and regulating factors of MAIT cells in alveolar echinococcosis (AE), a zoonotic parasitic disease by Echinococcus multilocularis (E. multilocularis) larvae chronically parasitizing liver organs, has not yet been studied. Blood samples (n=29) and liver specimens (n=10) from AE patients were enrolled. The frequency, phenotype, and function of MAIT cells in peripheral blood and liver tissues of AE patients were detected by flow cytometry. The morphology and fibrosis of liver tissue were examined by histopathology and immunohistochemistry. The correlation between peripheral MAIT cell frequency and serologic markers was assessed by collecting clinicopathologic characteristics of AE patients. And the effect of in vitro stimulation with E. multilocularis antigen (Emp) on MAIT cells. In this study, MAIT cells are decreased in peripheral blood and increased in the close-to-lesion liver tissues, especially in areas of fibrosis. Circulating MAIT exhibited activation and exhaustion phenotypes, and intrahepatic MAIT cells showed increased activation phenotypes with increased IFN-γ and IL-17A, and high expression of CXCR5 chemokine receptor. Furthermore, the frequency of circulating MAIT cells was correlated with the size of the lesions and liver function in patients with AE. After excision of the lesion site, circulating MAIT cells returned to normal levels, and the serum cytokines IL-8, IL-12, and IL-18, associated with MAIT cell activation and apoptosis, were altered. Our results demonstrate the status of MAIT cell distribution, functional phenotype, and migration in peripheral blood and tissues of AE patients, highlighting their potential as biomarkers and therapeutic targets.

Nidogen in development and disease.

Nidogen, also known as entactin, is a multifunctional glycoprotein that plays a crucial role in the maintenance of the basement membrane (BM), morphogenesis and neuronal plasticity. This review aims to provide an overview of the structural features, molecular interactions and diverse functions associated with Nidogen. As a bridging molecule within the BM, Nidogen acts as a linchpin connecting various extracellular matrix (ECM) components. Its involvement in tissue development, homeostasis, and pathological conditions underscores its biological and medical significance. We discuss the current state of knowledge regarding Nidogen's role in tissue maintenance, cell adhesion, migration, and signaling, shedding light on its intricate contributions to physiological and pathological processes.

Extrinsic apoptosis participates to tail regression during the metamorphosis of the chordate Ciona

Apoptosis is a regulated cell death ubiquitous in animals defined by morphological features depending on caspases. Two regulation pathways are described, currently named the intrinsic and the extrinsic apoptosis. While intrinsic apoptosis is well studied and considered ancestral among metazoans, extrinsic apoptosis is poorly studied outside mammals. Here, we address extrinsic apoptosis in the urochordates Ciona, belonging to the sister group of vertebrates. During metamorphosis, Ciona larvae undergo a tail regression depending on tissue contraction, migration and apoptosis. Apoptosis begin at the tail tip and propagates towards the trunk as a polarized wave. We identified Ci-caspase 8/10 by phylogenetic analysis as homolog to vertebrate caspases 8 and 10 that are the specific initiator of extrinsic apoptosis. We detected Ci-caspase 8/10 expression in Ciona larvae, especially at the tail tip. We showed that chemical inhibition of Ci-caspase 8/10 leads to a delay of tail regression, and Ci-caspase 8/10 loss of function induced an incomplete tail regression. The specificity between apoptotic pathways and initiator caspase suggests that extrinsic apoptosis regulates cell death during the tail regression. Our study presents rare in vivo work on extrinsic apoptosis outside mammals, and contribute to the discussion on its evolutionary history in animals.

Glioblastoma Cells Use an Integrin- and CD44-Mediated Motor-Clutch Mode of Migration in Brain Tissue.

Glioblastoma (GBM) is an aggressive malignant brain tumor with 2year survival rates of 6.7% (Stupp et al. in J Clin Oncol Off J Am Soc Clin Oncol 25:4127-4136, 2007; Mohammed et al. in Rep Pract Oncol Radiother 27:1026-1036, 2002). One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue (Lefranc et al. in J Clin Oncol Off J Am Soc Clin Oncol 23:2411-2422, 2005; Hoelzinger et al. in J Natl Cancer Inst 21:1583-1593, 2007). To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. Several models of cell migration have been proposed, including the motor-clutch, bleb-based motility, and osmotic engine models. Here we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify the mode of cell migration. We found that nearly all cell-vasculature interactions reflected pulling, rather than pushing, on vasculature at the cell leading edge, a finding consistent with a motor-clutch mode of migration, and inconsistent with an osmotic engine model or confined bleb-based migration. Reducing myosin motor activity, a key component in the motor-clutch model, was found to decrease migration speed at high doses for all cell types including U251 and 6 low-passage patient-derived xenograft lines (3 proneural and 3 mesenchymal subtypes). Variable responses were found at low doses, consistent with a motor-clutch mode of migration which predicts a biphasic relationship between migration speed and motor-to-clutch ratio. Targeting of molecular clutches including integrins and CD44 slowed migration of U251 cells. Overall we find that glioblastoma cell migration is most consistent with a motor-clutch mechanism to migrate through brain tissue ex vivo, and that both integrins and CD44, as well as myosin motors, play an important role in constituting the adhesive clutch. The online version contains supplementary material available at 10.1007/s12195-024-00799-x.

MgO@polydopamine Nanoparticle-Loaded Photothermal Microneedle Patches Combined with Chitosan Gel Dressings for the Treatment of Infectious Wounds.

As for wound drug delivery, microneedles (MNs) have attracted wide attention. However, while effective at increasing the depth of drug delivery, traditional MNs often have limited drug loads and have difficulty penetrating scabs on wounds. Herein, we develop a drug delivery system combining MgO@polydopamine (MgO@PDA) nanoparticle-loaded photothermal MN patches and chitosan (CS) gel to inhibit the formation of scabs and deliver sufficient drugs into deep tissue. When inserted into the wound, the MN system can keep the wound bed moist and weakly acidic to inhibit the formation of scabs and accelerate wound closure. The released MgO@PDA nanoparticles from both the tips and the backing layer, which immensely increase the drug load, continuously release Mg2+ in the moist, weakly acidic wound bed, promoting tissue migration and the formation of microvessels. MgO@PDA nanoparticles show excellent antibacterial activity under near-infrared irradiation synergized with the CS gel, and the PDA coating can also overcome the adverse effects of oxidative stress. Through in vitro and in vivo experiments, the MN system showed remarkable antibacterial, antioxidant, anti-inflammatory, and pro-angiogenic effects, indicating its potential in the treatment of infectious wounds.