CD146,a therapeutic target involved in cell plasticity

Since its identification as a marker for advanced melanoma in the 1980s,CD146 has been found to have multiple functions in both physiological and pathological processes,including embryonic development,tissue repair and regeneration,tumor progression,fibrosis disease,and inflammations.Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or coreceptor in these processes.This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis,prognosis,and targeted therapy.To better comprehend the versatile roles of CD146,we have summarized its research history and synthesized findings from numerous reports,proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development,regeneration,and various diseases.Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases.Therefore,the development of therapy targeting CD146 holds significant practical value.

CREB1 contributes colorectal cancer cell plasticity by regulating lnc RNA CCAT1 and NF-κB pathways

The CREB1 gene encodes an exceptionally pleiotropic transcription factor that frequently dysregulated in human cancers.CREB1 can regulate tumor cell status of proliferation and/or migration;however,the molecular basis for this switch involvement in cell plasticity has not fully been understood yet.Here,we first show that knocking out CREB1 triggers a remarkable effect of epithelial-mesenchymal transition(EMT)and leads to the occurrence of inhibited proliferation and enhanced motility in HCT116colorectal cancer cells.By monitoring 45 cellular signaling pathway activities,we find that multiple growth-related pathways decline significantly while inflammatory pathways including NF-κB are largely upregulated in comparing between the CREB1wild-type and knocked out cells.Mechanistically,cells with CREB1 knocked out show downregulation of MYC as a result of impaired CREB1-dependent transcription of the oncogenic lnc RNA CCAT1.Interestingly,the unbalanced competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted,which induces an obvious EMT phenotype of the cancer cells.Taken together,these studies identify previously unknown mechanisms of CREB1 in CRC cell plasticity via regulating lnc RNA CCAT1 and NF-κB pathways,providing a critical insight into a combined strategy for CREB1-targeted tumor therapies.

Non-coding RNAs regulate tumor cell plasticity

Tumor metastasis is one of the most serious challenges for human cancers as the majority of deaths caused by cancer are associated with metastasis,rather than the primary tumor.Recent studies have demonstrated that tumor cell plasticity plays a critical role in tumor metastasis by giving rise to various cell types which is necessary for tumor to invade adjacent tissues and form distant metastasis.These include differentiation of cancer stem cells(CSCs),or epithelial-mesenchymal transition(EMT)and its reverse process,mesenchymal-epithelial transition(MET).A growing body of evidence has demonstrated that the biology of tumor cell plasticity is tightly linked to functions of non-coding RNAs(ncRNAs),especially microRNAs(miRNAs)and long non-coding RNAs(lncRNAs).Therefore,understanding the mechanisms how non-coding RNAs regulate tumor cell plasticity is essential for discovery of new diagnostic markers and therapeutic targets to overcome metastasis.

Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury,substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer

Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog （Pten） and transforming growth factor-beta receptor type 2 （Tgfbr2） may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo. Tgfbr2 ablation abolished TGF-β signaling but increased the bone morphogenetic protein （BMP） signaling pathway through the negative regulator Tmeff1. Furthermore, increased BMP signaling promotes expression of the tumor marker genes ID1, Oct4, Nanog, and Sox2; ID1/STAT3/NANOG expression was inversely correlated with patient survival. Thus, our findings provide information about the molecular mechanisms by which BMP signaling pathways render stemness capacity to prostate tumor cells.

Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem

As a field we have made tremendous strides in treating breast cancer,with a decline in the past 30 years of overall breast cancer mortality.However,this progress is met with little affect once the disease spreads beyond the primary site.With a 5-year survival rate of 22%,10-year of 13%,for those patients with metastatic breast cancer(mBC),our ability to effectively treat wide spread disease is minimal.A major contributing factor to this ineffectiveness is the complex make-up,or heterogeneity,of the primary site.Within a primary tumor,secreted factors,malignant and pre-malignant epithelial cells,immune cells,stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis.Furthermore,heterogeneity contributes to our lack of understanding regarding the cells'remarkable ability to undergo epithelial/non-cancer stem cell(CSC)to mesenchymal/CSC(E-M/CSC)plasticity.The enhanced invasion&motility,tumor-initiating potential,and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis.While most work trying to understand E-M/CSC plasticity has been done on malignant cells,recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process.Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor.Moreover,we will discuss how one may potentially target these populations,ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.

Synthesis and characterization of novel low band-gap polymers containing squaraine units

Novel conjugated polymers based on squaric acid having 2,5-Bis[（E）-N-alkylpyrrol-2-ylvinyl]-3-alkylthiophene （PVTVP） unit in the main chain were successfully synthesized in good yields through polycondensation reaction. Their molecular structures were characterized by PT-IR and IH NMR. They have good solubility in common organic solvents, good thermal stability by thermal gravimetric analysis and high molecular weights. Their optical properties were investigated by UV-vis absorption spectra in CH2C12 solution, the results indicated all these compounds showed broad and strong spectral responses from 200 nm to 900 nm, suggesting their potential for application as organic plastic solar cells.

Notch4 participates in mesenchymal stem cell-induced differentiation in 3D-printed matrix and is implicated in eccrine sweat gland morphogenesis

Background:Eccrine sweat gland(SG)plays a crucial role in thermoregulation but exhibits very limited regenerative potential.Although SG lineage-restricted niches dominate SG morphogenesis and benefit SG regeneration,rebuilding niches in vivo is challenging for stem cell therapeutic applications.Hence,we attempted to screen and tune the critical niche-responding genes that dually respond to both biochemical and structural cues,which might be a promising strategy for SG regeneration.Methods:An artificial SG lineage-restricted niche consisting of mouse plantar dermis homogenates(i.e.biochemical cues)and 3D architecture(i.e.structural cues)was built in vitro by using an extrusion-based 3D bioprinting approach.Mouse bone marrow-derived mesenchymal stem cells(MSCs)were then differentiated into the induced SG cells in the artificial SG lineage-restricted niche.To decouple biochemical cues from structural cues,the transcriptional changes aroused by pure biochemical cues,pure structural cues and synergistic effects of both cues were analyzed pairwise,respectively.Notably,only niche-dual-responding genes that are differentially expressed in response to both biochemical and structural cues and participate in switching MSC fates towards SG lineage were screened out.Validations in vitro and in vivo were respectively conducted by inhibiting or activating the candidate niche-dual-responding gene(s)to explore the consequent effects on SG differentiation.Results:Notch4 is one of the niche-dual-responding genes that enhanced MSC stemness and pro-moted SG differentiation in 3D-printed matrix in vitro.Furthermore,inhibiting Notch4 specifically reduced keratin 19-positive epidermal stem cells and keratin 14-positive SG progenitor cells,thus further delaying embryonic SG morphogenesis in vivo.Conclusions:Notch4 not only participates in mouse MSC-induced SG differentiation in vitro but is also implicated in mouse eccrine SG morphogenesis in vivo.

Cancer stem cells may contribute to the difficulty in treating cancer

Tumour heterogeneity is a phenomenon where each cell that makes up a tumour,contains mutations that differ from that of other cells in the tumour.The clonal evolution and cancer stem cell theories of cancer formation,have been used to explain tumour heterogeneity.The theories both point to the existence of cells within a tumour that are capable of initiating the tumour in a different location.While the clonal evolution theory argues that all cells within a tumour possess this ability,the cancer stem cell theory argues that only a few cells(cancer stem cells or CSCs)within the tumour possess this ability to seed the tumour in a different location.Data supporting the cancer stem cell theory is accumulating.Researchers have targeted these CSCs therapeutically,hypothesizing that since these CSCs are the‘drivers’of tumour progression,their death may inhibit tumour progression.This was foiled by tumour cell plasticity,a phenomenon whereby a non-CSC spontaneously de-differentiates into a CSC.Researchers are now working on combinations that kill both CSCs and non-CSCs as well as drugs that prevent non-CSC-to-CSC transition.This review concisely describes CSCs and how they contribute to the difficulty in treating cancer.

Dual recombinases-based genetic lineage tracing for stem cell research with enhanced precision

Stem cell research has become a hot topic in biology,as the understanding of stem cell biology can provide new insights for both regenerative medicine and clinical treatment of diseases.Accurately deciphering the fate of stem cells is the basis for understanding the mechanism and function of stem cells during tissue repair and regeneration.Cre-loxP-mediated recombination has been widely applied in fate mapping of stem cells for many years.However,nonspecific labeling by conventional cell lineage tracing strategies has led to discrepancies or even controversies in multiple fields.Recently,dual recombinase-mediated lineage tracing strategies have been developed to improve both the resolution and precision of stem cell fate mapping.These new genetic strategies also expand the application of lineage tracing in studying cell origin and fate.Here,we review cell lineage tracing methods,especially dual genetic approaches,and then provide examples to describe how they are used to study stem cell fate plasticity and function in vivo.

Effects of test levels on creep and relaxation characteristic parameters of stem for rice seedlings grown in plastic cell tray

Creep and relaxation characteristics of stem for rice seedlings grown in plastic cell tray were studied by static tensile testing,in order to determine the relationship between characteristic parameters(rheological model parameters,stress components and strain components)and test levels(stress levels and strain levels).Rice seedling stem specimen used in the test was 40 mm in length.And the applied test values for the creep and relaxation test ranged from 1.0-3.0 MPa and 1.5%-3.5%,respectively,each for 5 levels.The results indicated that elastic modulus in the creep and relaxation model was not affected by test levels.However,except that viscosity coefficientηkv was a constant andηm1 decreased with the increase of test levels,other viscosity coefficient and rheological time nonlinearly increased as the test levels increased.And strain components in the creep model and stress components in the relaxation model significantly increased as the test levels increased.

When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

The role of fatty acid metabolism,including both anabolic and catabolic reactions in cancer has gained increas-ing attention in recent years.Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis,therapeutic resistance and relapse.Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population.This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations.Therefore,these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters,which are often refractory to cancer treatment and difficult to target.Moreover,interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging.This review highlights recent findings on the relationship between fatty acid metabolism,cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

Endogenous repair theory enriches construction strategies for orthopaedic biomaterials:a narrative review

The development of tissue engineering has led to new strategies for mitigating clinical problems;however,the design of the tissue engineering materials remains a challenge.The limited sources and inadequate function,potential risk of microbial or pathogen contamination,and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering.However,endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue.These cells exhibit remarkable plasticity,and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation.After a comprehensive review,we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration.Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair.This review discusses the effects of endogenous cells,especially stem cells,on injured tissue repairing,and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone,cartilage,and intervertebral disc regeneration.