The Plasticity of Nanofibrous Matrix Regulates Fibroblast Activation in Fibrosis

xloma.fota13 shared this article with you from Inoreader The Plasticity of Nanofibrous Matrix Regulates Fibroblast Activation in Fibrosis Via Advanced Healthcare Materials Little attention has been paid on the effect of matrix fiber‐network plasticity at microscale. Native fibrotic tissues show decreased plasticity. Using a plasticity‐controlled 3D culture system, we demonstrated that the decrease of matrix plasticity promoted fibroblast activation and spreading, which was mediated through cytoskeletal tension and nuclear translocation of yes associated protein. Abstract Natural extracellular matrix (ECM) mostly has a fibrous structure that supports and mechanically interacts with local residing cells to guide their behaviors. The effect of ECM elasticity on cell behaviors has been extensively investigated, while less attention has been paid to the effect of matrix fiber‐network plasticity at microscale, although plastic remodeling of fibrous matrix is a common phenomenon in fibrosis. Here, a significant decrease is found in plasticity of native fibrotic tissues, which is associated with an increase in matrix crosslinking. To explore the role of plasticity in fibrosis development, a set of 3D collagen nanofibrous matrix with constant modulus but tunable plasticity is constructed by adjusting the crosslinking degree. Using plasticity‐controlled 3D culture models, it is demonstrated that the decrease of matrix plasticity promotes fibroblast activation and spreading. Further, a coarse‐grained molecular dynamic model is developed to simulate the cell–matrix interaction at microscale. Combining with molecular experiments, it is revealed that the enhanced fibroblast activation is mediated through cytoskeletal tension and nuclear translocation of Yes‐associated protein. Taken together, the results clarify the effects of crosslinking‐induced plasticity changes of nanofibrous matrix on the development of fibrotic diseases and highlight plasticity as an important mechanical cue in understanding cell–matrix interactions. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Photocrosslinked, Tunable Protein Vesicles for Drug Delivery Applications

xloma.fota13 shared this article with you from Inoreader Photocrosslinked, Tunable Protein Vesicles for Drug Delivery Applications Via Advanced Healthcare Materials Photocrosslinked and tunable protein vesicles are self‐assembled from thermally responsive elastin‐like polypeptide fusion protein and fluorescent fusion protein. The size and swelling behavior of protein vesicles are tuned by altering protein hydrophobicity and ionic strength. The resulting vesicles achieve dual delivery of doxorubicin and fluorescent protein in vitro. Abstract Recombinant proteins have emerged as promising building blocks for vesicle self‐assembly because of their versatility through genetic manipulation and biocompatibility. Vesicles composed of thermally responsive elastin‐like polypeptide (ELP) fusion proteins encapsulate cargo during assembly. However, vesicle stability in physiological environments remains a significant challenge for biofunctional applications. Here, incorporation of an unnatural amino acid, para‐azido phenylalanine, into the ELP domain is reported to enable photocrosslinking of protein vesicles and tuning of vesicle size and swelling. The size of the vesicles can be tuned by changing ELP hydrophobicity and ionic strength. Protein vesicles are assessed for their ability to encapsulate doxorubicin and dually deliver doxorubicin and fluorescent protein in vitro as a proof of concept. The resulting photocrosslinkable vesicles made from full‐sized, functional proteins show high potential in drug delivery applic ations, especially for small molecule/protein combination therapies or targeted therapies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Advances in Micro/Nanoporous Membranes for Biomedical Engineering

xloma.fota13 shared this article with you from Inoreader Advances in Micro/Nanoporous Membranes for Biomedical Engineering Via Advanced Healthcare Materials Micro/nanoporous membranes (M/N‐PMs) present quite practical and potential value for extensive biological and medical applications involving separation, patterning, tissue reconstruction, high‐throughput manipulation/analysis, and biosensing. In this work, the recent advances in fundamentals of M/N‐PMs, as well as their applications in biomedical engineering are systematically summarized, providing insights into membrane design, microdevice establishment, and further performance. Abstract Porous membrane materials at the micro/nanoscale have exhibited practical and potential value for extensive biological and medical applications associated with filtration and isolation, cell separation and sorting, micro‐arrangement, in‐vitro tissue reconstruction, high‐throughput manipulation and analysis, and real‐time sensing. Herein, an overview of technological development of micro/nanoporous membranes (M/N‐PMs) is provided. Various membrane types and the progress documented in membrane fabrication techniques, including the electrochemical‐etching, laser‐based technology, microcontact printing, electron beam lithography, imprinting, capillary force lithography, spin coating, and microfluidic molding are described. Their key features, achievements, and limitations associated with micro/nanoporous membrane (M/N‐PM) preparation are discussed. The recently popularized applications of M/N‐PMs in biomedical engineering involving the separation of cells and biomole cules, bioparticle operations, biomimicking, micropatterning, bioassay, and biosensing are explored too. Finally, the challenges that need to be overcome for M/N‐PM fabrication and future applications are highlighted. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cell‐Laden Gradient Hydrogel Scaffolds for Neovascularization of Engineered Tissues

xloma.fota13 shared this article with you from Inoreader Cell‐Laden Gradient Hydrogel Scaffolds for Neovascularization of Engineered Tissues Via Advanced Healthcare Materials Vascular cell‐laden gradient PEG hydrogels with five types of gradient combinations including immobilized cell adhesion peptide concentration (RGD), stiffness, and protease‐sensitivity are designed to investigate their role on spatial variations in vascular sprouting responses in 3D culture Abstract Gradients in mechanical properties, physical architecture and biochemical composition exist in a variety of complex tissues, yet 3D in vitro models that enable investigation of these cues on cellular processes, especially those contributing to vascularization of engineered tissues are limited. Here, a photopolymerization approach to create cell‐laden hydrogel biomaterials with decoupled and combined gradients in modulus, immobilized cell adhesive peptide (RGD) concentration, and proteolytic degradation enabling spatial encapsulation of vascular spheroids is reported to elucidate their impact on vascular sprouting in 3D culture. Vascular spheroids encapsulated in these gradient scaffolds exhibit spatial variations in total sprout length. Scaffolds presenting an immobilized RGD gradient promote biased vascular sprouting toward increasing RGD concentration. Importantly, biased sprouting is found to be dependent on immobilized RGD gradient characteristics, including magnitude and sl ope, with increases in these factors contributing to significant enhancements in biased sprouting responses. Conversely, reduction in biased sprouting responses is observed in combined gradient scaffolds possessing opposing gradients in RGD and modulus. The presented work is the first to demonstrate the use of a cell‐laden biomaterial platform to systematically investigate the role of multiple scaffold gradients as well as gradient slope, magnitude and orientation on vascular sprouting responses in 3D culture. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

2D Nanomaterials for Tissue Engineering and Regenerative Nanomedicines: Recent Advances and Future Challenges

xloma.fota13 shared this article with you from Inoreader 2D Nanomaterials for Tissue Engineering and Regenerative Nanomedicines: Recent Advances and Future Challenges Via Advanced Healthcare Materials 2D nanomaterial‐based therapeutic strategies applied in tissue engineering and regenerative nanomedicines are discussed. Recent advances in the application of 2D nanomaterial‐based hydrogels, nanosheets, scaffolds, or drug delivery systems that engineered to repair skin, bone, cartilage, and other types of tissues are discussed along with the current challenges and future prospects. Abstract Regenerative medicine has become one of the hottest research topics in medical science that provides a promising way for repairing tissue defects in the human body. Due to their excellent physicochemical properties, the application of 2D nanomaterials in regenerative medicine has gradually developed and has been attracting a wide range of research interests in recent years. In particular, graphene and its derivatives, black phosphorus, and transition metal dichalcogenides are applied in all the aspects of tissue engineering to replace or restore tissues. This review focuses on the latest advances in the application of 2D‐nanomaterial‐based hydrogels, nanosheets, or scaffolds that are engineered to repair skin, bone, and cartilage tissues. Reviews on other applications, including cardiac muscle regeneration, skeletal muscle repair, nerve regeneration, brain disease treatment, and spinal cord healing are also provided. The challenges and prospects of applications of 2D nanomater ials in regenerative medicine are discussed. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

NSCs Migration Promoted and Drug Delivered Exosomes‐Collagen Scaffold via a Bio‐Specific Peptide for One‐Step Spinal Cord Injury Repair

xloma.fota13 shared this article with you from Inoreader NSCs Migration Promoted and Drug Delivered Exosomes‐Collagen Scaffold via a Bio‐Specific Peptide for One‐Step Spinal Cord Injury Repair Via Advanced Healthcare Materials MExos are found to promote the migration of neural stem cells. Using MExos as drug carriers to kill two birds with one stone, a multifunctional MExos‐collagen scaffold via dual bio‐specific tethering ability of a novel peptide is designed. The scaffold demonstrates superior performance for complete spinal cord repair in rats. Abstract Spinal cord injury (SCI) is plaguing medical professionals globally due to the complexity of injury progression. Based on tissue engineering technology, there recently emerges a promising way by integrating drugs with suitable scaffold biomaterials to mediate endogenous neural stem cells (NSCs) to achieve one‐step SCI repair. Herein, exosomes extracted from human umbilical cord‐derived mesenchymal stem cells (MExos) are found to promote the migration of NSCs in vitro/in vivo. Utilizing MExos as drug delivery vehicles, a NSCs migration promoted and paclitaxel (PTX) delivered MExos‐collagen scaffold is designed via a novel dual bio‐specificity peptide (BSP) to effectively retain MExos within scaffolds. By virtue of the synergy that MExos recruit endogenous NSCs to the injured site, and PTX induce NSCs to give rise to neurons, this multifunctional scaffold has shown superior performance for motor functional recovery after complete SCI in rats by enhancing neural regene ration and reducing scar deposition. Besides, the dual bio‐specific peptide demonstrates the capacity of tethering other cells‐derived exosomes on collagen scaffold, such as erythrocytes‐derived or NSCs‐derived exosomes on collagen fibers or membranes. The resulting exosomes‐collagen scaffold may serve as a potential multifunctional therapy modality for various disease treatments including SCI. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Discrepancies on the Role of Oxygen Gradient and Culture Condition on Mesenchymal Stem Cell Fate

xloma.fota13 shared this article with you from Inoreader Discrepancies on the Role of Oxygen Gradient and Culture Condition on Mesenchymal Stem Cell Fate Via Advanced Healthcare Materials This progress report surveys the literature and discusses the conflicting results on the effect of oxygen exposure during cell culture that affect mesenchymal stem cell function and few promising strategies are suggested that when combined with hypoxic culture would facilitate consistent results. Abstract Over the past few years, mesenchymal stem (or stromal) cells (MSCs) have garnered enormous interest due to their therapeutic value especially for their multilineage differentiation potential leading to regenerative medicine applications. MSCs undergo physiological changes upon in vitro expansion resulting in expression of different receptors, thereby inducing high variabilities in therapeutic efficacy. Therefore, understanding the biochemical cues that influence the native local signals on differentiation or proliferation of these cells is very important. There have been several reports that in vitro culture of MSCs in low oxygen gradient (or hypoxic conditions) upregulates the stemness markers and promotes cell proliferation in an undifferentiated state, as hypoxia mimics the conditions the progenitor cells experience within the tissue. However, different studies report different oxygen gradients and culture conditions causing ambiguity in their interpretation of the results. In this progress report, it is aimed to summarize recent studies in the field with specific focus on conflicting results reported during the application of hypoxic conditions for improving the proliferation or differentiation of MSCs. Further, it is tried to decipher the factors that can affect characteristics of MSC under hypoxia and suggest a few techniques that could be combined with hypoxic cell culture to better recapitulate the MSC tissue niche. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mesopore to Macropore Transformation of Metal–Organic Framework for Drug Delivery in Inflammatory Bowel Disease

xloma.fota13 shared this article with you from Inoreader Mesopore to Macropore Transformation of Metal–Organic Framework for Drug Delivery in Inflammatory Bowel Disease Via Advanced Healthcare Materials A mechanism for inflammation‐targeting drug delivery by Ce‐MOF@PSS is proposed. Negatively charged Ce‐MOF@PSS nanoparticles selectively adhere to inflamed tissue. Reactive oxygen species produced by activated immune cells at the inflamed mucosa induces transformation of Ce‐MOF@PSS from mesoporous to macroporous and local drug release. Specific drug delivery exhibits superior therapeutic effect over free drug administration. Abstract Inflammatory bowel disease (IBD) is a chronic relapsing autoimmune disease that is characterized by segmental intestinal inflammation. There is an urgent need for more efficient inflammation‐targeting strategies to improve therapeutic effect and reduce systemic drug exposure. Herein, an oxidation‐responsive metal–organic framework material (Ce‐MOF@PSS) is reported that preferentially adheres to inflamed intestine via enema. The overproduced reactive oxygen species (ROS) at inflammatory sites induces transformation of Ce‐MOF@PSS from mesopore to macropore with local drug release. In experimental colitis, the Ce‐MOF@PSS delivery system exhibits excellent inflammation‐targeting efficacy and superior therapeutic effect over free drug on suppressing inflammation and repairing intestinal barrier function. Accordingly, by targeting intestinal inflammation, increasing local drug concentrations, scavenging ROS, reducing systemic exposure, and exhibiting excellent safety profi les, it is considered that the Ce‐MOF drug delivery platform can be intensively developed as a translational nanomedicine for the management of IBD and other inflammatory diseases. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

LIF Maintains mESC Pluripotency by Modulating TET1 and JMJD2 Activity in a JAK2‐Dependent Manner

xloma.fota13 shared this article with you from Inoreader LIF Maintains mESC Pluripotency by Modulating TET1 and JMJD2 Activity in a JAK2‐Dependent Manner Via STEM CELLS JAK2 is the key mediator of LIF‐mediated epigenetic control in mESC pluripotency and maintenance. JAK2 activation by LIF induces its translocation to the nucleus. Activated JAK2 directly interacts with core epigenetic enzymes TET1 and JMJD2, modulating its activity and promotes the DNA and histone demethylation, respectively. JAK2 also induces DNMTs phosphorylation and primes it for degradation. All together, these JAK2‐mediated effects establish an open epigenetic status in the pluripotency genes promoter regions. Abstract The LIF‐JAK2‐STAT3 pathway is the central signal transducer that maintains undifferentiated mouse ESCs (mESCs), which is achieved by the recruitment of activated STAT3 to the master pluripotency genes and activation of the gene transcriptions. It remains unclear, however, how the epigenetic status required for the master gene transcriptions is built into LIF‐treated mESC cultures. In this study, Jak2, but not Stat3, in the LIF canonical pathway, establishes an open epigenetic status in the pluripotency gene promoter regions. Upon LIF activation, cytosolic JAK2 was translocalized into the nucleus of mESCs, and reduced DNA methylation (5mC levels) along with increasing DNA hydroxymethylation (5hmC) in the pluripotent gene (Nanog/Pou5f1) promoter regions. In addition, the repressive histone codes H3K9m3/H3K27m3 were reduced by JAK2. Activated JAK2 directly interacted with the core epigenetic enzymes TET1 and JMJD2, modulating its activity and promotes the DNA and histone demethylation, respectively. The JAK2 effects were attained by tyrosine phosphorylation on the epigenetic enzymes. The effects of JAK2 phosphorylation on the enzymes were diverse, but all were merged to the epigenetic signatures associated with open DNA/chromatin structures. Taken together, these results reveal a previously unrecognized epigenetic regulatory role of JAK2 as an important mediator of mESC maintenance. © AlphaMed Press 2021 Significance Statement This study reveals underappreciated JAK2‐mediated epigenetic control in maintaining mESC pluripotency. JAK2 activation by LIF induce JAK2 translocation to nucleus where it directly interacts with epigenetic regulator protein which ultimately affect the DNA and histone methylation of pluripotent genes. Briefly, JAK2 primed DNMT2 for degradation, while inducing activation of TET1 and JMJD2 that ultimately open the epigenetic status in the pluripotent genes promoter regions. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Niche‐dependent inhibition of neural stem cell proliferation and oligodendrogenesis is mediated by the presence of myelin basic protein

xloma.fota13 shared this article with you from Inoreader Niche‐dependent inhibition of neural stem cell proliferation and oligodendrogenesis is mediated by the presence of myelin basic protein Via STEM CELLS Myelin basic protein (MBP) presented in the spinal cord niche, but not the brain niche, causes the release of an inhibitory factor that regulates neural precursor cell kinetics and oligodendrogenesis. Hence, regionally distinct niches along the neuraxis respond differently to the same protein (MBP) and regulate cell behavior. Abstract Neural stem and progenitor cells (collectively termed neural precursor cells [NPCs]) are found along the ventricular neuraxis extending from the spinal cord to the forebrain in regionally distinct niches comprised of different cell types, architecture, and cell‐cell interactions. An understanding of the factors that regulate NPC behavior is critical for developing therapeutics to repair the injured central nervous system. Herein, we demonstrate that myelin basic protein (MBP), the major cytoplasmic protein constituent of the myelin sheath in oligodendrocytes, can regulate NPC behavior. Under physiological conditions, NPCs are not in contact with intracellular MBP; however, upon injury, MBP is released into the neural parenchyma. We reveal that MBP presented in a spinal cord niche is inhibitory to NPC proliferation. This inhibitory effect is regionally distinct as spinal cord NPCs, but not forebrain‐derived NPCs, are inhibited by MBP. We performed coculture and conditioned medi a experiments that reveal the stem cell niche is a key regulator of MBP's inhibitory actions on NPCs. The inhibition is mediated by a heat‐labile protein released by spinal cord niche cells, but not forebrain niche cells. However, forebrain NPCs are also inhibited by the spinal cord derived factor as revealed following in vivo infusion of the spinal cord niche‐derived conditioned media. Moreover, we show that MBP inhibits oligodendrogenesis from NPCs. Together, these findings highlight the role of MBP and the regionally distinct microenvironment in regulating NPC behavior which has important implications for stem cell‐based regenerative strategies. © AlphaMed Press 2021 Significance Statement Neural precursor cells (NPCs) reside in regionally distinct niches in the central nervous system (CNS). The niche regulates NPC behavior in homeostatic and injury conditions. This study shows that myelin basic protein (MBP), a major constituent of myelin sheaths in the CNS, regulates NPC behavior in a niche dependent fashion. In vitro and in vivo studies reveal that MBP presented in the spinal cord niche, but not the brain niche, results in the release of a protein that inhibits NPC proliferation and oligogenesis. Hence, regionally distinct niches respond differently to the same protein (MBP), by releasing factors that regulate NPCs throughout the CNS. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The miR‐200 family is required for ectodermal organ development through the regulation of the epithelial stem cell niche

xloma.fota13 shared this article with you from Inoreader The miR‐200 family is required for ectodermal organ development through the regulation of the epithelial stem cell niche Via STEM CELLS The LaCL stem cell niche does not express miR‐200, which regulates Sox2 expression. Progenitor cells exiting the stem cell niche start expressing miR‐200 to promote differentiation and the specification of cell fates for mature tooth development. miR‐200 therefore acts to compartmentalize the stem cell niche Abstract The murine lower incisor ectodermal organ contains a single epithelial stem cell (SC) niche that provides epithelial progenitor cells to the continuously growing rodent incisor. The dental stem cell niche gives rise to several cell types and we demonstrate that the miR‐200 family regulates these cell fates. The miR‐200 family is highly enriched in the differentiated dental epithelium and absent in the stem cell niche. In this study, we inhibited the miR‐200 family in developing murine embryos using new technology, resulting in an expanded epithelial stem cell niche and lack of cell differentiation. Inhibition of individual miRs within the miR‐200 cluster resulted in differential developmental and cell morphology defects. miR‐200 inhibition increased the expression of dental epithelial stem cell markers, expanded the stem cell niche and decreased progenitor cell differentiation. RNA‐seq. identified miR‐200 regulatory pathways involved in cell differentiation and compartmentalization of the stem cell niche. The miR‐200 family regulates signaling pathways required for cell differentiation and cell cycle progression. The inhibition of miR‐200 decreased the size of the lower incisor due to increased autophagy and cell death. New miR‐200 targets demonstrate gene networks and pathways controlling cell differentiation and maintenance of the stem cell niche. This is the first report demonstrating how the miR‐200 family is required for in vivo progenitor cell proliferation and differentiation. © AlphaMed Press 2021 Significance Statement Current microRNA (miR) inhibition methods cannot be used to study in vivo developmental stem cell processes. CRISPR‐Cas genome editing cannot specifically knockout a miR within a cluster. Furthermore, not all miRs, especially within introns can be targeted by the CRISPR method without affecting gene expression. ES cells have been profiled for miR expression; however, cell‐based assays using oligonucleotides targeting miRs are not specific and are toxic. The authors developed a highly specific, effective miR inhibitor that can be used to knockdown miRs during embryonic development to determine their effect on stem cells, cell proliferation, and differentiation. The authors show that the miR‐200 family acts to compartmentalize an ectodermal stem cell niche by regulating progenitor cell differentiation during development. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.