Mechanical microenvironments as key cellular regulator in the liver

Tissue stiffness, shear stress, and interstitial pressure make up major factors of liver mechanical microenvironment, which play the key regulatory role to control cell behaviors in the liver and progress of liver diseases. In this review, we focus on the characteristics of liver mechanical microenvironments and summarize cellular responses to mechanobiological changes during liver pathogenesis, especially in hepatic fibrosis and cirrhosis. A better understanding of the indispensable contributions of mechanical cues to liver homeostasis and pathogenesis is significant to identify new therapeutic targets for liver diseases such as hepatic fibrosis or cirrhosis.

In situ self-assembled organoid for osteochondral tissue regeneration with dual functional units

The regeneration of hierarchical osteochondral units is challenging due to difficulties in inducing spatial,directional and controllable differentiation of mesenchymal stem cells(MSCs)into cartilage and bone compartments.Emerging organoid technology offers new opportunities for osteochondral regeneration.In this study,we developed gelatin-based microcryogels customized using hyaluronic acid(HA)and hydroxyapatite(HYP),respectively for inducing cartilage and bone regeneration(denoted as CH-Microcryogels and OS-Microcryogels)through in vivo self-assembly into osteochondral organoids.The customized microcryogels showed good cytocompatibility and induced chondrogenic and osteogenic differentiation of MSCs,while also demonstrating the ability to self-assemble into osteochondral organoids with no delamination in the biphasic cartilage-bone structure.Analysis by mRNA-seq showed that CH-Microcryogels promoted chondrogenic differentiation and inhibited inflammation,while OS-Microcryogels facilitated osteogenic differentiation and suppressed the immune response,by regulating specific signaling pathways.Finally,the in vivo engraftment of pre-differentiated customized microcryogels into canine osteochondral defects resulted in the spontaneous assembly of an osteochondral unit,inducing simultaneous regeneration of both articular cartilage and subchondral bone.In conclusion,this novel approach for generating self-assembling osteochondral organoids utilizing tailor-made microcryogels presents a highly promising avenue for advancing the field of tissue engineering.

Key considerations on the development of biodegradable biomaterials for clinical translation of medical devices:With cartilage repair products as an example

With the interdisciplinary convergence of biology,medicine and materials science,both research and clinical translation of biomaterials are progressing at a rapid pace.However,there is still a huge gap between applied basic research on biomaterials and their translational products-medical devices,where two significantly different perspectives and mindsets often work independently and non-synergistically,which in turn significantly increases financial costs and research effort.Although this gap is well-known and often criticized in the biopharmaceutical industry,it is gradually widening.In this article,we critically examine the developmental pipeline of biodegradable biomaterials and biomaterial-based medical device products.Then based on clinical needs,market analysis,and relevant regulations,some ideas are proposed to integrate the two different mindsets to guide applied basic research and translation of biomaterial-based products,from the material and technical perspectives.Cartilage repair substitutes are discussed here as an example.Hopefully,this will lay a strong foundation for biomaterial research and clinical translation,while reducing the amount of extra research effort and funding required due to the dissonance between innovative basic research and commercialization pipeline.

Consistent apparent Young’s modulus of human embryonic stem cells and derived cell types stabilized by substrate stiffness regulation promotes lineage specificity maintenance

Background:Apparent Young’s modulus(AYM),which reflects the fundamental mechanical property of live cells measured by atomic force microscopy and is determined by substrate stiffness regulated cytoskeletal organization,has been investigated as potential indicators of cell fate in specific cell types.However,applying biophysical cues,such as modulating the substrate stiffness,to regulate AYM and thereby reflect and/or control stem cell lineage specificity for downstream applications,remains a primary challenge during in vitro stem cell expansion.Moreover,substrate stiffness could modulate cell heterogeneity in the single-cell stage and contribute to cell fate regulation,yet the indicative link between AYM and cell fate determination during in vitro dynamic cell expansion(from single-cell stage to multi-cell stage)has not been established.Results:Here,we show that the AYM of cells changed dynamically during passaging and proliferation on substrates with different stiffness.Moreover,the same change in substrate stiffness caused different patterns of AYM change in epithelial and mesenchymal cell types.Embryonic stem cells and their derived progenitor cells exhibited distinguishing AYM changes in response to different substrate stiffness that had significant effects on their maintenance of pluripotency and/or lineage-specific characteristics.On substrates that were too rigid or too soft,fluctuations in AYM occurred during cell passaging and proliferation that led to a loss in lineage specificity.On a substrate with‘optimal’stiffness(i.e.,3.5 kPa),the AYM was maintained at a constant level that was consistent with the parental cells during passaging and proliferation and led to preservation of lineage specificity.The effects of substrate stiffness on AYM and downstream cell fate were correlated with intracellular cytoskeletal organization and nuclear/cytoplasmic localization of YAP.Conclusions:In summary,this study suggests that optimal substrate stiffness regulated consistent AYM during passaging and proliferation reflects and contributes to hESCs and their derived progenitor cells lineage specificity maintenance,through the underlying mechanistic pathways of stiffness-induced cytoskeletal organization and the downstream YAP signaling.These findings highlighted the potential of AYM as an indicator to select suitable substrate stiffness for stem cell specificity maintenance during in vitro expansion for regenerative applications.

Injectable bone marrow microniches by co-culture of HSPCs with MSCs in 3D microscaffolds promote hematopoietic reconstitution from acute lethal radiation

Hematopoietic syndrome of acute radiation syndrome(h-ARS)is an acute illness resulted from the damage of bone marrow(BM)microenvironment after exposure to radiation.Currently,the clinical management of h-ARS is limited to medication-assisted treatment,while there is still no specific therapy for the hematopoietic injury from high-dose radiation exposure.Our study aimed to assemble biomimetic three-dimensional(3D)BM microniches by co-culture of hematopoietic stem and progenitor cells(HSPCs)and mesenchymal stem cells(MSCs)in porous,injectable and viscoelastic microscaffolds in vitro.The biodegradable BM microniches were then transplanted in vivo into the BM cavity for the treatment of h-ARS.We demonstrated that the maintenance of HSPCs was prolonged by co-culture with MSCs in the porous 3D microscaffolds with 84μm in pore diameter and 11.2 kPa in Young’s modulus compared with 2D co-culture system.Besides,the minimal effective dose and therapeutic effects of the BM microniches were investigated on a murine model of h-ARS,which showed that the intramedullary cavity-injected BM microniches could adequately promote hematopoietic reconstitution and mitigate death from acute lethal radiation with a dose as low as 1000 HSPCs.Furthermore,the mRNA expression of Notch1 and its downstream target gene Hes1 of HSPCs were increased when co-cultured with MSCs,while the Jagged1 expression of the co-cultured MSCs was upregulated,indicating the significance of Notch signaling pathway in maintenance of HSPCs.Collectively,our findings provide evidence that biomimetic and injectable 3D BM microniches could maintain HSPCs,promote hematopoiesis regeneration and alleviate post-radiation injury,which provides a promising approach to renovate conventional HSPCs transplantation for clinical treatment of blood and immune disorders.

Direct intercellular communications dominate the interaction between adipose-derived MSCs and myofibroblasts aqainst cardiac fibrosis

The onset of cardiac fibrosis post myocardial infarction greatly impairs the function of heart. Recent advances of cell transplantation showed great benefits to restore myocardial function, among which the mesenchymal stem cells （MSCs） has gained much attention. However, the underlying cellular mechanisms of MSC therapy are still not fully understood. Although paracrine effects of MSCs on residual cardiomyocytes have been discussed, the amelioration of fibrosis was rarely studied as the hostile environment cannot support the survival of most cell populations and impairs the diffusion of soluble factors. Here in order to decipher the potential mecha- nism of MSC therapy for cardiac fibrosis, we investi- gated the interplay between MSCs and cardiac myofibroblasts （mFBs） using interactive co-culture method, with comparison to paracrine approaches, namely treatment by MSC conditioned medium and gap co-culture method. Various fibrotic features of mFBs were analyzed and the most prominent anti-fibrosis effects were always obtained using direct co-culture that allowed cell-to-cell contacts. Hepatocyte growth factor （HGF）, a well-known anti-fibrosis factor, was demonstrated to be a major contributor for MSCs＇ anti-fibrosisfunction. Moreover, physical contacts and tube-like structures between MSCs and mFBs were observed by live cell imaging and TEM which demonstrate the direct cellular interactions.

Biomaterials as carrier, barrier and reactor for cell-based regenerative medicine

Cell therapy has achieved tremendous success in regenerative medicine in the past several decades. However, challenges such as cell loss, death and immune-rejection after transplantation still persist. Bio- materials have been designed as carriers to deliver cells to desirable region for local tissue regeneration; as barriers to protect transplanted cells from host immune attack; or as reactors to stimulate host cell recruitment, homing and differentiation. With the assistance of bio- materials, improvement in treatment efficiency has been demonstrated in numerous animal models of degener- ative diseases compared with routine free cell-based therapy. Emerging clinical applications of biomaterial assisted cell therapies further highlight their great pro- mise in regenerative therapy and even cure for complex diseases, which have been failed to realize by conven- tional therapeutic approaches.

A low dose cell therapy system for treating osteoarthritis:In vivo study and in vitro mechanistic investigations

Mesenchymal stem cells(MSCs)can be effective in alleviating the progression of osteoarthritis(OA).However,low MSC retention and survival at the injection site frequently require high doses of cells and/or repeated injections,which are not economically viable and create additional risks of complications.In this study,we produced MSC-laden microcarriers in spinner flask culture as cell delivery vehicles.These microcarriers containing a low initial dose of MSCs administered through a single injection in a rat anterior cruciate ligament(ACL)transection model of OA achieved similar reparative effects as repeated high doses of MSCs,as evaluated through imaging and histological analyses.Mechanistic investigations were conducted using a co-culture model involving human primary chondrocytes grown in monolayer,together with MSCs grown either within 3D constructs or as a monolayer.Co-culture supernatants subjected to secretome analysis showed significant decrease of inflammatory factors in the 3D group.RNA-seq of co-cultured MSCs and chondrocytes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis revealed processes relating to early chondrogenesis and increased extracellular matrix interactions in MSCs of the 3D group,as well as phenotypic maintenance in the co-cultured chondrocytes.The cell delivery platform we investigated may be effective in reducing the cell dose and injection frequency required for therapeutic applications.

State of the art in flexible SERS sensors toward label-free and onsite detection:From design to applications

Surface-enhanced Raman scattering(SERS)as a powerful non-invasive spectroscopic technique has been intensively used in bio/chemical sensing,enabling ultrasensitive detection of various analytes and high specificity with a fingerprint-like characteristic.Flexible SERS sensors conformally adapting to nonplanar surfaces and allowing swab-sampling or in-situ detection of analytes,which are not achievable for rigid SERS sensors,greatly meet the demand of onsite and real-time diagnostics.However,the rational design and fabrication of flexible SERS-based sensors for point-of-care diagnostics aiming to simultaneously achieve extremely high sensitivity,stability,and good signal reproducibility remain many challenges.We present a state-of-the-art review of the flexible SERS sensors.Attentions are devoted to engineering plasmonic substrates for improving the performance of flexible SERS devices.Strategies of constructing the flexible SERS sensors toward point-of-care detection are investigated in depth.Advanced algorithms assisting the SERS data process are also presented for intelligently distinguishing the species and contents of analytes.The promising applications of flexible SERS sensors in medical diagnostics,environmental analyses,food safety,and forensic science are displayed.The flexible SERS devices serving as powerful analytical tools shed new light on the in-situ and point-of-care detection of real-world analytes in a convenient,facile,and non-destructive manner,and especially are conceivable to serve as next-generation wearable sensors for healthcare.

From the water sources of the Tibetan Plateau to the ocean:State of nutrients in the Changjiang linked to land use changes and climate variability

Anthropogenic activity is an important driver of changes in the chemistry of nutrients(N,P,and Si)over watersheds at the sub-continental scale(e.g.,106km~2)and can markedly modify their seaward fluxes to the global ocean.In the present study,we reviewed the current status of nutrient chemistry in Changjiang(Yangtze River)based on data collected through 11 expeditions along a river course spanning 4,500 km and 15–20 major tributaries during 1997–2016 as well as monthly monitoring at the river mouth since 1980.The data were analyzed together with published results in the literature to synthesize the recent developments and current state of nutrients in the Changjiang.Previously published results from the Qinghai-Tibetan Plateau head waters were included to realize the systematics of nutrients for the whole drainage basin.Here,we showed that tributaries of the upper reaches of watersheds collectively determine the regime with high concentration and skewed species ratio of nutrients in the Changjiang mainstream,producing profound effects over a water course of 2,000–2,500 km further downstream and until the river mouth.Moreover,using data across the Three Gorges Reservoir(TGR)during 2003–2016,we evaluated the trapping and/or amplifying effects of the Three Gorges Dam(TGD)on nutrient chemistry.Tide-influenced river delta contributed an additional 20%dissolved inorganic phosphorus and 5–10%dissolved inorganic nitrogen and dissolved silicates to the seaward flux,dramatically affecting the stoichiometry of nutrients at the river mouth.Next,based on compiled data on supply and export,legacy nutrients were evaluated.Both nitrogen and phosphorus are in the accumulation phase over the watersheds,and the legacy nutrient fluxes are much higher than the annual riverine seaward fluxes.Finally,we demonstrated that the seaward fluxes of anthropogenic nutrients from the Changjiang exceed those from other top 10 largest rivers on this planet,which can be attributed to land use changes in the China over the last three to four decades.

Underlying topography and forest height estimation from SAR tomography based on a nonparametric spectrum estimation method with low sidelobes

The underlying topography and forest height play an indispensable role in many fields,including geomorphology,civil engineering construction,forest investigation,and the modeling of natural disasters.As a new microwave remote sensing technology with three-dimensional imaging capability,synthetic aperture radar(SAR)tomography(TomoSAR)has already been proven to be an important tool for underlying topography and forest height estimation.Many spectrum estimation methods have now been proposed for TomoSAR.However,most of the commonly used methods are susceptible to noise and inevitably produce sidelobes,resulting in a reduced accuracy for the inversion of forest structural parameters.In this paper,to solve this problem,a nonparametric spectrum estimation method with low sidelobes-the G-Pisarenko method-is introduced.This method performs a logarithmic operation on the covariance matrix to obtain the main scattering characteristics of the objects of interest while suppressing the noise as much as possible.The effectiveness of the proposed method is demonstrated by the use of both simulated data and P-band airborne SAR data from a tropical forest region in Gabon,Africa.The results show that the proposed method can reduce the sidelobes and improve the estimation accuracy for the underlying topography and forest height.

Comparing GWAS and Brain Structure-Specific Gene Expression Profiles Identifies Psychiatric Disorder-Related Brain Structures at Different Developmental Stages

Dear Editor,Psychiatric disorders are a group of mental disorders characterized by psychological or behavioral disabilities.Losing of the ability to work and assuming the extensive cost of long-term treatment,patients with psychiatric disorders are forced to support a heavy financial and medical burden.The growth and development of brain structures are dynamic,and different brain structures have major and specific functions to control behavior and performance.

Precise cell therapy for liver fibrosis: Endothelial cell and macrophage therapy

Liver fibrosis is typically caused by chronic viral hepatitis and,more recently,fatty liver disease associated with obesity.There are currently no approved drugs for liver cirrhosis,and liver transplantation is limited by donor scarcity,thus driving the investigation of novel therapeutic strategies.The development of liver fibrosis presents with stage-and zone-dependent characteristics that manifest as distinct dynamic changes during vascularization and extracellular matrix(ECM)deposition.However,current cellular therapies do not consider the spatiotem-poral variations of liver fibrosis without identifying the precise location and stage to administer the intervention to achieve optimal therapeutic effects.Herein,we focus on endothelial cell(EC)and macrophage therapy for liver fibrosis because of their important roles in regulating the spatiotemporal changes of vascularization and ECM deposition during liver fibrosis progression.Overall,this review summarizes the stage-dependent EC and macrophage therapy for liver fibrosis,elucidates their respective mechanisms,and exemplifies potential strategies to realize precise cell therapy by targeting specific liver zones.

Artificial intelligence-based ultrasound imaging technologies for hepatic diseases

Ultrasound(US)imaging is a non-invasive,real-time,economical,and convenient imaging modality that has been widely used in diagnosing and treating hepatic diseases.Artificial intelligence(AI)technology can predict or make decisions based on the experience of clinical experts and knowledge obtained from training data.This technology can help clinicians improve the detection efficiency and evaluate hepatic diseases,promote clinical treatment of the liver,and predict the response of the liver after treatment.This review summarizes the current rapid development of US technology and related AI methods in the diagnosis and treatment of hepatic diseases.Covered topics include steatosis grading,fibrosis staging,detection of focal liver lesions,US image segmentation,multimodal image registration,and other applications.At present,the field of AI in US imaging is still in its early stages.With the future progress of AI technology,AI-based US imaging can further improve diagnosis,reduce medical costs,and optimize US-based clinical workflow.This technology has broad prospects for application to hepatic diseases.