Generation of Model Tissues with Dendritic Vascular Networks via Sacrificial Laser-Sintered Carbohydrate Templates

Jordan Miller’s team consistently produces outstanding publications highlighting the core of biomedical research: the intersect between engineering and biology. In this paper, vascular networks were produced using 3D-printed, laser-sintered, carbohydrate vessels that would then be “sacrificed” to produce hollow lumens. This process is capable of producing incredible channel complexity where the sacrificed carbohydrate structures allow for the establishment of an endothelial layer of cells in the vessel. As a whole, the process offers an approach to vascularizing engineered tissues. Read the Paper >

Multivariate Patterning of Human Pluripotent Cells Under Perfusion Reveals Critical Roles of Induced Paracrine Factors in Kidney Organoid Development

In cellular biology we are often “spoiled for choice” with the number of factors to test in a given experiment. The authors of this work devised a high-throughput microfluidic device that they used to grow 3D kidney organoid structures. The device allowed for hundreds of unique tests to be completed with minimal user input while using accessible imaging techniques to quantify the organoids in the system. This article demonstrates a workflow applicable to a wide range of tissues by navigating complex experiments and arriving at an optimized condition. Read the Paper >

Stirred Suspension Bioreactors Maintain Naïve Pluripotency of Human Pluripotent Stem Cells

An excellent paper published by the Rancourt lab in Calgary, Alberta—a group I have previously collaborated with. By directing PSCs towards a naïve state, the authors were able to demonstrate an improved expansion rate in suspension cultures while maintaining their pluripotency. This work addresses the important challenge of scaling-up PSC cell sources that can be used as a building block for downstream differentiation. Read the Paper >

Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration

Alveolar Type II cells are the regenerative stem cell population in the alveoli, the gas-exchange portion of the lungs. For several decades, scientists have known that Type II cells are able to differentiate to Type I cells in order to regenerate after lung injury, but there is still a lot that remains unknown about the transition from Type II to Type I cells. In this paper, the authors used single cell RNA sequencing to map the transition from Type II to Type I cells and identify a subset of Type II cells (DATPs) that constitute a transient intermediate that is prevented from fully differentiating to Type I cells if inflammation persists. Read the paper >

Persistence of a Regeneration-Associated, Transitional Alveolar Epithelial Cell State in Pulmonary Fibrosis

Related to the above paper, this paper also identifies an intermediate cell type between Type II and Type I cells that is responsive to TP63, is more vulnerable to DNA damage, and shows hallmarks of senescence. These PATS cells were found in higher numbers in the lungs of advanced pulmonary fibrosis patients, a disease which has no cure. Whether the PATS population is the same exact population as the DATP population in the paper above remains to be determined, but further understanding of PATS and DATP cells could have significant implications for pulmonary fibrosis research and treatment. Read the paper >

Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction

Use of human stem cell-derived organoids is relatively new in the lung biology field. Katsura et al., as well as several other groups, have found that stem cell-derived lung organoids are a useful model system for many lung pathologies, including COVID-19. In this paper the authors show that lung organoids express the SARS-CoV-2 co-receptor ACE2 and identified IFN-gamma as a potential therapeutic target for COVID-19 treatment. Read the paper >

Species-Specific Segmentation Clock Periods Are Due to Differential Biochemical Reaction Speeds

Significant strides have been made to understand the reason for different developmental tempo among mammals. The Ebisuya group at EMBL Barcelona studied mouse and human interspecies differences by recreating segmentation clocks in species-specific iPS cells. Assessments at the orthologous core locus of the segmentation clock, HES7, determined that the differences are not due to distinct nucleotide or protein-coding sequences. Rather, biochemical reactions that increased protein stability and cell cycle in human cells correlated with a twofold slower rate of human cell differentiation compared to mouse cells. A companion article by Rayon et al. in the same journal issue substantiates the Ebisuya group’s conclusion using a different system. Read the copy >

Extensive Germline Genome Engineering in Pigs

Generation of xeno-transplantable organs may have taken a big step toward reality. An international collaboration of research groups exploited CRISPR-Cas9 and transposon technologies to produce engineered pigs with three deleted porcine xeno-antigens and with a number of human transgenes to aid in immunological compatibility. In addition, the pigs were engineered with inactivating mutations to coding-competent and potentially virulent copies of porcine endogenous retroviruses present in their genome. Overall, this work may enable xeno-transplantation of pig organs into humans, which have previously been prone to rejection. Read the paper >

Transient Inhibition of mTOR in Human Pluripotent Stem Cells Enables Robust Formation of Mouse-Human Chimeric Embryos

Researchers based in Buffalo, NY have shown that briefly inhibiting mTOR using Torin1 caused primed human pluripotent stem cells to revert to the naive state. When these cells were transplanted into mouse blastocysts, the arising mice contained up to 4% human cells. The human cells appeared to contribute to all three germ layers, including a large number of enucleated red blood cells. Interestingly, the incorporated human cells sped up their development pace to match that of the mouse cells. Read the paper >

Spatially Regulated Editing of Genetic Information Within a Neuron

For the first time, researchers have shown that editing of nucleic acids may take place upon messenger RNA (mRNA) in the cytoplasm. The Rosenthal group found that the editing of mRNA in the cytoplasm of squid neurons is mediated by ADAR2 (adenosine deaminase that acts on RNA). Curiously, >70% of sites capable of being edited are preferentially edited in the giant axon in comparison to cell bodies. The ability to edit mRNA in the cytoplasm is yet another approach in the tool box of nucleic acid editing technologies. Read the paper >

CRISPR Interference-Based Platform for Multimodal Genetic Screens in Human iPSC-Derived Neurons

Neurons are a vital player in our day-to-day functioning, but their post-mitotic nature makes them difficult to study on a large scale. A collaboration between UCSF and the NIH tackled this problem by using CRISPR interference screens on iPSC-derived neurons. The authors were the first to conduct this kind of study on healthy, non-cancerous neurons, allowing the elucidation of gene functions under normal conditions. One important takeaway from this study is that even key housekeeping genes behave very differently in stem cells and neurons, proving the importance of context in genetics. This methodology promises to unlock the secrets of neural development and neurodegeneration, with many potential applications across other tissues. Read the paper >

Glia-to-Neuron Conversion by CRISPR-CasRx Alleviates Symptoms of Neurological Disease in Mice

This research by Hui Yang et al. suggests that the reversal of debilitating neurodegenerative disorders may lie in a single transcriptional switch. Using viral delivery of the CRISPR system CasRx to downregulate the transcription of polypyrimidine tract-binding protein 1 (Ptbp1) in injured mouse retinas, the team was able to convert Müller glia cells into retinal glia cells. The same tactic was also able to generate dopaminergic neurons in the substantia nigra, reversing some of the motor defects associated with Parkison’s disease. While the technique is still in its early days, this study shows that Ptbp1 knockdown could offer treatment for neuronal loss disorders. Read the paper >

CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boosts Direct Glia-to-Neuron Conversion

‘Mitochondria are the powerhouse of the cell’ is a phrase common in biology textbooks, but new evidence suggests they may also be key to neuronal reprogramming. Scientists at Ludwig Maximilians University Munich and Helmholtz Zentrum München identified approximately 150 significantly enriched mitochondrial proteins from both neurons and astrocytes. By using a dCas9 system to activate these proteins early in astrocyte-to-neuronal conversation, they were able to increase both the speed and efficiency of the process. This demonstrates the potential to replace neurons lost to neurodegenerative disease by generating them from a patient’s other tissues. Read the paper >