Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma.

Melanoma, the most lethal form of skin cancer, often has worse outcomes in older patients. We previously demonstrated that an age-related decrease in the secreted extracellular matrix (ECM) protein HAPLN1 has a role in slowing melanoma progression. Here we show that HAPLN1 in the dermal ECM is sufficient to maintain the integrity of melanoma-associated blood vessels, as indicated by increased collagen and VE-cadherin expression. Specifically, we show that HAPLN1 in the ECM increases hyaluronic acid and decreases endothelial cell expression of ICAM1. ICAM1 phosphorylates and internalizes VE-cadherin, a critical determinant of vascular integrity, resulting in permeable blood vessels. We found that blocking ICAM1 reduces tumor size and metastasis in older mice. These results suggest that HAPLN1 alters endothelial ICAM1expression in an indirect, matrix-dependent manner. Targeting ICAM1 could be a potential treatment strategy for older patients with melanoma, emphasizing the role of aging in tumorigenesis.

The Arp2/3 complex enhances cell migration on elastic substrates.

Cell migration on soft surfaces occurs in both physiological and pathological processes such as corticogenesis during embryonic development and cancer invasion and metastasis. The Arp2/3 complex in neural progenitor cells was previously demonstrated to be necessary for cell migration on soft elastic substrate but not on stiff surfaces, but the underlying mechanism was unclear. Here, we integrate computational and experimental approaches to elucidate how the Arp2/3 complex enables cell migration on soft surfaces. We found that lamellipodia comprised of a branched actin network nucleated by the Arp2/3 complex distribute forces over a wider area, thus decreasing stress in the substrate. Additionally, we found that interactions between parallel focal adhesions within lamellipodia prolong cell-substrate interactions by compensating for the failure of neighboring adhesions. Together with decreased substrate stress, this leads to the observed improvements in migratory ability on soft substrates in cells utilizing lamellipodia-dependent mesenchymal migration when compared with filopodia-based migration. These results show that the Arp2/3 complex-dependent lamellipodia provide multiple distinct mechanical advantages to gliomas migrating on soft 2D substrates, which can contribute to their invasive potential.

Ginkgo biloba extracts inhibit post-ischemic LTP through attenuating EPSCs in rat hippocampus.

Ginkgo biloba extract 761 (EGb761), a standardized extract from the Ginkgo biloba leaf, is purported to inhibit NMDA receptor-mediated neuronal excitotoxicity and protect neurons form ischemic injury. However, the specific signal pathway involved in the effects of EGb761 on synaptic plasticity is still in dispute. In this article, effects of EGb761 and its monomer component ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC) and quercetin on rat hippocampal synaptic plasticity were studied. The evoked Excitatory postsynaptic currents (EPSCs) and miniature EPSCs were recorded on hippocampal slices from SD rats (14-21 days of age) by whole-cell patch-clamp recording and long-term potentiation (LTP) was induced by theta-burst stimulation. Acutely applied EGb761 inhibited the LTP, but bilaterally affect the evoked EPSCs. The evoked EPSCs were increased by incubation of lower concentration of EGb761, then the evoked EPSCs were decreased by incubation of higher concentration of EGb761. EGb761 monomer component GA, GB and GC could also inhibit the TBS-induced LTP and EPSC amplitude but not paired-pulse ratio (PPR). But quercetin, another monomer component of EGb761, led to increase in EPSC amplitude and decrease in PPR. Simultaneously, EGb761 and its monomer component ginkgolides inhibited the post-ischemic LTP (i-LTP) by inhibiting the EPSCs and the AMPA receptor subunit GluA1 expression on postsynaptic membrane. The results indicated that high concentration of EGb761 might inhibit LTP and i-LTP through inhibition effects of GA, GB and GC on AMPA receptors.

Application of conductive PPy/SF composite scaffold and electrical stimulation for neural tissue engineering.

Electrical stimulation (ES) with conductive polymers can dramatically enhance neurite outgrowth and promote neural regeneration. However, besides ES, the practical applications of neural repair is also highly dependent on the nerve cell functionality and response to substrate conductivity. Therefore, the combination of the ES and suitable materials, such as tissue scaffolds, has been applied to facilitate treatment of neural injuries and demonstrated great potential in peripheral nerve regeneration. In this study, polypyrrole/silk fibroin (PPy/SF) conductive composite scaffold was fabricated by 3D bioprinting and electrospinning. Schwann cells seeded on these scaffolds were electrically stimulated and hence demonstrated enhanced viability, proliferation and migration, as well as upregulated expression of neurotrophic factors. Furthermore, the constructed PPy/SF conductive nerve guidance conduits accompanying with ES could effectively promote axonal regeneration and remyelination in vivo. Moreover, we found that the MAPKs signal transduction pathway was activated by ES at the conductive conduit. Our findings demonstrate that the PPy/SF conductive composite scaffolds with longitudinal guidance exhibit favorable properties for clinical use and promotes nerve regeneration and functional recovery.

Bioprinting of Stem Cells: Interplay of Bioprinting Process, Bioinks, and Stem Cell Properties.

Combining the advantages of 3D bioprinting technology and biological characteristics of stem cells, bioprinting of stem cells is recognized as a novel technology with broad applications in biological study, drug testing, tissue engineering, regenerative medicine, etc. However, the biological performance and functional reconstruction of stem cells are greatly influenced by both the bioprinting process and post-bioprinting culture conditions, which are critical factors to consider for further applications. Here we review the recent development of stem cell bioprinting technology and conclude on the major factors regulating stem cell viability, proliferation, differentiation, and function from the aspects of the choice of bioprinting techniques, the modulation of bioprinting parameters, and the regulation of the stem cell niche in the whole lifespan of bioprinting practices. We aim to provide a comprehensive consideration and guidance regarding the bioprinting of stem cells for optimization of this promising technology in biological and medical applications.