资源环境科技发展态势分析平台

Precise protein sequencing and folding are believed to generate the structure and chemical diversity of natural channels(1,2), both of which are essential to synthetically achieve proton transport performance comparable to that seen in natural systems. Geometrically defined channels have been fabricated using peptides, DNAs, carbon nanotubes, sequence-defined polymers and organic frameworks(3-13). However, none of these channels rivals the performance observed in their natural counterparts. Here we show that without forming an atomically structured channel, four-monomer-based random heteropolymers (RHPs)(14) can mimic membrane proteins and exhibit selective proton transport across lipid bilayers at a rate similar to those of natural proton channels. Statistical control over the monomer distribution in an RHP leads to segmental heterogeneity in hydrophobicity, which facilitates the insertion of single RHPs into the lipid bilayers. It also results in bilayer-spanning segments containing polar monomers that promote the formation of hydrogen-bonded chains(15,16) for proton transport. Our study demonstrates the importance of the adaptability that is enabled by statistical similarity among RHP chains and of the modularity provided by the chemical diversity of monomers, to achieve uniform behaviour in heterogeneous systems. Our results also validate statistical randomness as an unexplored approach to realize protein-like behaviour at the single-polymer-chain level in a predictable manner.

Metastasis requires cancer cells to undergo metabolic changes that are poorly understood(1-3). Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1(high) and MCT1(-/low) cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1(high) cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.

Macrophages are the first cells of the nascent immune system to emerge during embryonic development. In mice, embryonic macrophages infiltrate developing organs, where they differentiate symbiotically into tissue-resident macrophages (TRMs)(1). However, our understanding of the origins and specialization of macrophages in human embryos is limited. Here we isolated CD45(+) haematopoietic cells from human embryos at Carnegie stages 11 to 23 and subjected them to transcriptomic profiling by single-cell RNA sequencing, followed by functional characterization of a population of CD45(+)CD34(+)CD44(+) yolk sac-derived myeloid-biased progenitors (YSMPs) by single-cell culture. We also mapped macrophage heterogeneity across multiple anatomical sites and identified diverse subsets, including various types of embryonic TRM (in the head, liver, lung and skin). We further traced the specification trajectories of TRMs from either yolk sac-derived primitive macrophages or YSMP-derived embryonic liver monocytes using both transcriptomic and developmental staging information, with a focus on microglia. Finally, we evaluated the molecular similarities between embryonic TRMs and their adult counterparts. Our data represent a comprehensive characterization of the spatiotemporal dynamics of early macrophage development during human embryogenesis, providing a reference for future studies of the development and function of human TRMs.

Single-cell RNA sequencing of haematopoietic cells from human embryos at different developmental stages sheds light on the development and specification of macrophages in different tissues.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts(1). Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types(2,3). However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E-2 (PGE(2)). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE(2) drives the expansion omicron f a population of Sca-1(+) reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1(+) cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE(2) promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1(+) cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE(2)-Ptger4. Analyses of patient-derived organoids established that PGE(2)-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE(2)-Ptger4-Yap signalling axis.

Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E-2, which, when disrupted, prevented initiation of intestinal tumours.