Dandan Liu

Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 MAPK pathway.

Understanding the interaction mechanisms between nanomaterials and biological cells is important for the control and manipulation of these interactions for biomedical applications. In this study, we investigated the cellular effects of gold nanoparticles (AuNPs) on the differentiation of mesenchymal stem cells (MSCs) and the associated molecular mechanisms. The results showed that AuNPs promoted the differentiation of MSCs toward osteoblast cells over adipocyte cells by inducing an enhanced osteogenic transcriptional profile and an attenuated adipogenic transcriptional profile. AuNPs exerted the effects by interacting with the cell membrane and binding with proteins in the cytoplasm, causing mechanical stress on the MSCs to activate p38 mitogen-activated protein kinase pathway (MAPK) signaling pathway, which regulates the expression of relevant genes to induce osteogenic differentiation and inhibit adipogenic differentiation.

Inhibition of proliferation and differentiation of mesenchymal stem cells by carboxylated carbon nanotubes.

Multipotent mesenchymal stem cells (MSCs) have attracted substantial attention in stem cell therapy and tissue engineering due to their ability to be cultured for successive passages and multilineage differentiation. Carbon nanotubes (CNTs) have been proposed to be used as potential biomedical structures for bone formation. Therefore, it is important to study the mechanisms of interaction between MSCs and CNTs. We demonstrated that carboxylated single-walled carbon nanotubes (SWCNTs) and carboxylated multiwalled carbon nanotubes (MWCNTs) inhibited the proliferation, osteogenic differentiation, adipogenic differentiation, and mineralization of MSCs. Oxidative stress assay indicated that reactive oxygen species (ROS) may not be responsible for the observed cytotoxicity of carboxylated CNTs. Quantitative real-time polymerase chain reaction (Q-PCR) experiments confirmed that the expression of osteoblast specific genes and adipocyte differentiation specific genes was greatly attenuated during the differentiation of MSCs in the presence of carboxylated CNTs. TEM images revealed that CNTs might interact with proteins located on the cell membrane or in the cytoplasm, which have a further impact on subsequent cellular signaling pathways. Q-PCR results and Western blot analysis together verified that the inhibition of proliferation and osteogenic differentiation of MSCs may be modulated through a Smad-dependent bone morphogenetic protein (BMP) signaling pathway.

Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite

Potential bioaccumulation is one of the biggest limitations for silica nanodrug delivery systems in cancer therapy. In this study, a mesoporous silica nanoparticles/hydroxyapatite (MSNs/HAP) hybrid drug carrier, which enhanced the biodegradability of silica, was developed by a one-step method. The morphology and structure of the nanoparticles were characterized by TEM, DLS, FT-IR, XRD, N2 adsorption-desorption isotherms, and XPS, and the drug loading and release behaviors were tested. TEM and ICP-OES results indicate that the degradability of the nanoparticles has been significantly improved by Ca(2+) escape from the skeleton in an acid environment. The MSNs/HAP sample exhibits a higher drug loading content of about 5 times that of MSNs. The biological experiment results show that the MSNs/HAP not only exhibits good biocompatibility and antitumor effect but also greatly reduces the side effects of free DOX. The as-synthesized hybrid nanoparticles may act as a promising drug delivery system due to their good biocompatibility, high drug loading efficiency, pH sensitivity, and excellent biodegradability.

TGF-β/BMP signaling pathway is involved in cerium-promoted osteogenic differentiation of mesenchymal stem cells.

The extensive applications of cerium (Ce) increased the chance of human exposure to Ce and its compounds. It was reported that Ce was mainly deposited in the bone after administration. However, the potential effect and mechanism of Ce on bone metabolism are not well understood. In this study, we investigated the cellular effects of Ce on the differentiation of mesenchymal stem cells (MSCs) and the associated molecular mechanisms. The results indicated that Ce promoted the osteogenic differentiation and inhibited the adipogenic differentiation of MSCs at cell level. Genes involved in transforming growth factor‐β/bone morphogenetic proteins (TGF‐β/BMP) signaling pathway were significantly changed when the MSCs were exposed to 0.0001u2009µM Ce by RT2Profiler™ PCR Array analysis. The expression of genes and proteins related to pathways, osteogenic, and adipogenic biomarkers of MSCs upon interaction with Ce was further confirmed by quantitative real‐time reverse transcriptase polymerase chain reaction (Q‐PCR) and Western blot analysis. The results suggest that Ce exerts the effects by interacting with bone morphogenetic protein receptor (BMPR) and activates TGF‐β/BMP signaling pathway, leads to the up‐regulation of the osteogenic master transcription factor, runt‐related transcription factor 2 (Runx 2), and the down‐regulation of the adipocytic master transcription factor, peroxisome proliferator‐activated receptor gamma 2 (PPARγ2). Runx2, which subsequently up‐regulates osteoblast (OB) marker genes collagen I (Col I) and BMP2 at early stages, alkaline phosphatase (ALP), and osteocalcin (OCN) at later stages of differentiation, thus driving MSCs to differentiate into OBs. The results provide novel evidence to elucidate the mechanisms of bone metabolism by Ce. J. Cell. Biochem. 114: 1105–1114, 2013.

Gold nanoparticles stimulate differentiation and mineralization of primary osteoblasts through the ERK/MAPK signaling pathway.

Gold nanoparticles (AuNPs) have shown great promise for a variety of applications, including chemistry, biology, and medicine. Recently, AuNPs have found promising applications in cartilage and bone repair. However, to realize the above promised applications, more work needs to be carried out to clarify the interactions between biological systems and AuNPs. In the present study, primary osteoblasts were used to evaluate the biocompatibility of 20-nm and 40-nm AuNPs, including morphology, proliferation, differentiation, gene and protein expression, and the underlying mechanisms. The results demonstrated that AuNPs were taken up by osteoblasts and aggregated in perinuclear compartment and vescular structures, but no morphological changes were observed. AuNPs could significantly promote the proliferation of osteoblasts, enhance the ALP activities, and increase the number of bone nodules and calcium content in vitro. In addition, the expression of BMP-2, Runx-2, OCN and Col-1 was remarkably up-regulated in the presence of AuNPs. It is noteworthy that 20-nm AuNPs are more potent than 40-nm AuNPs in regulating osteoblast activities. Besides, AuNPs increased the level of ERK phosphorylation/total ERK, suggesting the activation of ERK/MAPK pathway is involved in above activities. In conclusion, AuNPs exhibited great biocompatibility with osteoblasts, and have tremendous potential to be used as drug and/or gene delivery carrier for bone and tissue engineering in the future.

Status of bi- and multi-nuclear platinum anticancer drug development.

Cisplatin has become one of the most commonly used compounds for the treatment of a wide spectrum of human malignancies. Unfortunately, cisplatin has several major drawbacks. Driven by the impressive impact of cisplatin on cancer chemotherapy, great efforts have been made to develop new derivatives with improved pharmacological properties. Among the over 30 platinum agents which have entered clinical trials after the onset of clinical studies with cisplatin in the early 1970s, only carboplatin and oxaliplatin have received worldwide approval so far, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval. It has become quite evident that mere analogues of cisplatin or carboplatin will not probably offer any substantial clinical advantages over the existing drugs. Therefore, people turned to synthesize non-classical platinum anticancer drugs which were capable of forming a different range of DNA adducts which could display a different spectrum of anticancer activity compared to cisplatin. This review will summarize the structural types and structure-activity rules of non-classical bi- and multi-nuclear platinum anticancer drugs, and discuss their future potential as anticancer agents.

Reorganization of cytoskeleton and transient activation of Ca2+ channels in mesenchymal stem cells cultured on silicon nanowire arrays.

Tissue engineering combines biological cells and synthetic materials containing chemical signaling molecules to form scaffolds for tissue regeneration. Mesenchymal stem cells (MSCs) provide an attractive source for tissue engineering due to their versatility of multipotent differentiation. Recently, it has been recognized that both chemical and mechanical stimulations are essential mediators of adhesion and differentiation of MSCs. While significant progress has been made on the understanding of chemical regulatory factors within the extracellular matrix, the effects of mechanical stimulation exerted by nanomaterials on MSCs and the underlying mechanisms are less well-known. The present study showed that the adhesion, proliferation, and differentiation of MSCs cultured on vertically aligned silicon nanowire (SiNW) arrays were significantly different from those on flat silicon wafer and control substrates. The interactions between MSCs and the SiNW arrays caused the stem cells to preferentially differentiate toward osteocytes and chondrocytes but not adipocytes in the absence of supplementary growth factors. Our study demonstrated that Ca(2+) ion channels were transiently activated in MSCs upon mechanical stimulation, which eventually led to activation of Ras/Raf/MEK/ERK signaling cascades to regulate adhesion, proliferation, and differentiation of MSCs. The stretch-mediated transient Ca(2+) ion channel activation and cytoskeleton reorganization during stem cell-nanowire interaction may be early events of lineage-specific potentiation of MSCs in determining the fates of mesenchymal stem cells cultured on microenvironments with specific mechanical properties.

Activation of multiple signaling pathways during the differentiation of mesenchymal stem cells cultured in a silicon nanowire microenvironment

UNLABELLEDnMesenchymal stem cells (MSC) offer an optimal source for bone tissue engineering due to their capability of undergoing multilineage differentiation, where the mechanical properties of the microenvironment of MSCs are vital for osteochondral formation. However, the mechanisms of how mechanical and microenvironmental cues control osteogenesis and chondrogenesis are yet to be elucidated. In this study, we investigated the effects of vertically aligned silicon nanowire (SiNW) array on the differentiation of MSCs and the associated molecular mechanisms involved in osteogenesis and chandrogenesis. The results showed that the microenvironment of SiNW array activated a number of mechanosensitive pathways (including Integrin, TGF-β/BMP, Akt, MAPK, Insulin, and Wnt pathways) in MSCs, which converged to stimulate the osteogenesis and chondrogenesis via the Ras-Raf-MEK-ERK cascade.nnnFROM THE CLINICAL EDITORnThis study reports on the mechanisms and microenvironmental influence of osteogenesis and chondrogenesis by mesenchymal stem cells interacting with vertically aligned silicon nanowire scaffolds.

Status of Non-Classical Mononuclear Platinum Anticancer Drug Development

Cisplatin has become one of the most commonly used compounds for the treatment of a wide spectrum of human malignancies. Unfortunately, cisplatin has several major drawbacks. Driven by the impressive impact of cisplatin on cancer chemotherapy, great efforts have been made to develop new derivatives with improved pharmacological properties. Among the over 30 platinum agents which have entered clinical trials after the onset of clinical studies with cisplatin in the early 1970s, only carboplatin and oxaliplatin have received worldwide approval so far, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval. It has become quite evident that mere analogues of cisplatin or carboplatin will not probably offer any substantial clinical advantages over the existing drugs. Consequently, attention turned to the synthesis of non-classical platinum anticancer drugs which were capable of forming a different range of DNA adducts which could display a different spectrum of anticancer activity compared to cisplatin. The status of non-classical bi- and multi-nuclear platinum anticancer drug development has been reviewed. This review will summarize the structural types and structure-activity of non-classical mononuclear platinum anticancer drugs, and discuss their future potential as anticancer agents.

Microfluidic Platform for Studying Chemotaxis of Adhesive Cells Revealed a Gradient-Dependent Migration and Acceleration of Cancer Stem Cells

Recent studies reveal that solid tumors consist of heterogeneous cells with distinct phenotypes and functions. However, it is unclear how different subtypes of cancer cells migrate under chemotaxis. Here, we developed a microfluidic device capable of generating multiple stable gradients, culturing cells on-chip, and monitoring single cell migratory behavior. The microfluidic platform was used to study gradient-induced chemotaxis of lung cancer stem cell (LCSC) and differentiated LCSC (dLCSC) in real time. Our results showed the dynamic and differential response of both LCSC and dLCSC to chemotaxis, which was regulated by the β-catenin dependent Wnt signaling pathway. The microfluidic analysis showed that LCSC and dLCSC from the same origin behaved differently in the same external stimuli, suggesting the importance of cancer cell heterogeneity. We also observed for the first time the acceleration of both LCSC and dLCSC during chemotaxis caused by increasing local concentration in different gradients, which could only be realized through the microfluidic approach. The capability to analyze single cell chemotaxis under spatially controlled conditions provides a novel analytical platform for the study of cellular microenvironments and cancer cell metastasis.