The generation of organoids is one of the biggest scientific advances in regenerative medicine. Here, by lengthening the time that human pluripotent stem cells (hPSCs) were exposed to a three-dimensional microenvironment, and by applying defined renal inductive signals, we generated kidney organoids that transcriptomically matched second-trimester human fetal kidneys. We validated these results using ex vivo and in vitro assays that model renal development. Furthermore, we developed a transplantation method that utilizes the chick chorioallantoic membrane. This approach created a soft in vivo microenvironment that promoted the growth and differentiation of implanted kidney organoids, as well as providing a vascular component. The stiffness of the in ovo chorioallantoic membrane microenvironment was recapitulated in vitro by fabricating compliant hydrogels. These biomaterials promoted the efficient generation of renal vesicles and nephron structures, demonstrating that a soft environment accelerates the differentiation of hPSC-derived kidney organoids. This work has recieved the prestigious award Íñigo Álvarez de Toledo in Basic Nephrology 2019. It has also been highlighted as a News and Views in the same journal Nature Materials and as an Editorial Comment in the prestigious journal Nature Reviews in Nephrology.
Every year, a committee of experts sits down with a tough job to do: from among all ICREA publications, they must find a handful that stand out from all the others. This is indeed a challenge. The debates are sometimes heated and always difficult but, in the end, a shortlist of 24 publications is produced. No prize is awarded, and the only additional acknowledge is the honour of being chosen and highlighted by ICREA. Each piece has something unique about it, whether it be a particularly elegant solution, the huge impact it has in the media or the sheer fascination it generates as a truly new idea. For whatever the reason, these are the best of the best and, as such, we are proud to share them here.
LIST OF SCIENTIFIC HIGHLIGHTS
Accelerating the derivation of kidney organoids from human pluripotent stem cells (2019)
Montserrat Pulido, Núria (IBEC)view details
Trepat, Xavier (IBEC)
Keep-on moving: Evaluating the multiple conformations of enzymes (2019)
Osuna Oliveras, Sílvia (UdG)view details
Enzymes are proteins that are capable of accelerating the chemical reactions by as many as seventeen orders of magnitude. These molecules that have the ability to speed reactions are called catalysts.
How do enzymes work? The understanding of the enormous catalytic power of biocatalysts still corresponds to one of the grand challenges of chemical biology. Experimental and computational evidences have demonstrated that enzymes can adopt multiple conformations in solution, which are key for their function. We have demonstrated that by evaluating the multiple conformations that enzymes adopt by means of computational tools such as Molecular Dynamics (MD) simulations their mechanism of action can be elucidated. Additionally, these simulations can be used for predicting which changes in their structure (mutations) are required for novel activity.
New target for liver cancer treatment: Our computational studies have provided further evidence for the structural and functional similarity between different p38 kinases. One of the kinase enzymes, p38gamma, was found to present similitudes with another group of proteins known as CDKs, which have been known for a long time to be responsible for regulating the cell division cycle. This study demonstrates that p38gamma could be a new pharmacological target for liver cancer.
New enzymes for the synthesis of contraceptive hormones: Many of the drugs used to treat diseases have limitations in the production process. In most cases, many by-products are obtained that have no pharmacological activity, dramatically reducing the production efficiency. In a recent study we aimed to produce a key intermediate in the synthesis of drugs used as contraceptive hormones, Levonorgestel or Gestodene. X-ray crystallography studies together with computational tools made possible the design of a new Alcohol Dehydrogenase (ADH) enzymes for the efficient synthesis of the steroid hormone precursors. We found dramatic differences in the mobility of a region of the enzyme that was essential for enhancing the enzyme activity towards these industrially-relevant substrates.
Changes in the CO2 regulating capacity of the Southern Ocean (2019)
Pelejero Bou, Carles (CSIC - ICM)view details
Today, the world’s oceans absorb about one-third of the CO2 that we humans are putting into the atmosphere from the combustion of fossil fuels. Among them, the Southern Ocean is the one that contributes most to this sequestration. Almost half of all the oceanic CO2 uptake takes place in the Southern Ocean. This absorption is, of course, very positive; otherwise we would have significantly higher CO2 concentrations in the atmosphere, with the consequent enhanced global warming. However, the Southern Ocean has not always operated in this way. This is what we have discovered in this study, which provides a reconstruction of the CO2 regulating capacity of the Southern Ocean over the last 25.000 years. For this, we analyzed specific isotopic ratios of planktonic microfossils (Fig. 1) and several key organic compounds from a deep sea sediment core recovered south of Tasmania (Fig. 2). With these analyses we reconstructed the evolution of parameters such as seawater temperature (from long chain alkenones) and the acidity (from boron isotopes) in the past. With them, we calculated the variability of the dissolved CO2 in seawater which, by comparison with the record of atmospheric CO2 from Antarctica ice cores, allowed us to determine the CO2 sink or source role of the Southern Ocean during the last glacial to interglacial transition. The results show that the Southern Ocean surface waters in the studied location were a net sink for atmospheric CO2 during glacial times and up until about 12.000 years ago, when they became a net source of CO2 for about 8.000 years. In this varying regulatory role of the Southern Ocean, key factors were the changes in primary productivity and the intensity of marine currents. This study helps to understand the variability of this regulatory role of the Southern Ocean but also alerts about the future capacity of this ocean to continue to absorb CO2, which should not necessarily continue to be as favorable as today. In the event that its capacity to act as a CO2 sink decreased in the future, the global projections on the emissions of this greenhouse gas would be altered to even more alarming levels than the current ones.
A common mechanism regulates inflammation in opposing directions in tissue regeneration and cancer (2019)
Postigo, Antonio (IDIBAPS)view details
Inflammation is a normal response of the body to infections and injury. The migration into the inflamed tissue of some cells of our immune system known as macrophages is a requisite for the elimination of cell debris and the subsequent regeneration of injured tissues. Tissue regeneration most often involves the activation of “stem cells” that are normally in a quiescent stage. We found that a protein named ZEB1 both protects skeletal muscle from damage and is required for its regeneration. ZEB1 promotes the transition of macrophages toward an anti-inflammatory and pro-regenerative status in acute and chronic (muscular dystrophies) injured skeletal muscles. ZEB1 is also required for muscle stem cells to maintain their quiescent status. These results established ZEB1 as an important factor in the regulation of inflammatory response and in improving the regenerative capacity of stem cells, opening new avenues in the treatment of muscular dystrophies (Siles et al., 2019).
However, continuous inflammation is at the root of many diseases. Thus, chronic inflammation of some tissues, such as the liver, pancreas or colon, is a known risk factor for the development of cancer. We found that ZEB1 is required for the inflammation of the colon. We found that, contrary to what occurs in skeletal muscle, ZEB1 promotes (rather than inhibits) chronic inflammation and its progression toward cancer. ZEB1 causes the inflammation of the epithelial cells in the colon (a disease known as ulcerative colitis) and contributes to their subsequent transformation into cancer cells. ZEB1 triggers inflammation by inducing lesions in the DNA of the cell but also by inhibiting our body's self-repair mechanisms as it prevents the repair of DNA lesions through the inhibition of an enzyme called MPG. This work unveils a new mechanism in the link between inflammation and cancer and can help to develop new strategies in the treatment of ulcerative colitis and of other chronic inflammatory conditions that are risk factors in cancer development (de Barrios et al 2019).
Towards Data-Integrated Cell (2019)
Przulj, Natasa (BSC-CNS)view details
We propose a novel, data-driven concept of an integrated cell, iCell, that integrates several types of systems-level genomic data. We construct iCells of cancers and the corresponding healty tissues. We identify new genes involved in cancer, many of which have previously been of unknown function and cannot be identified as different in cancer in any specific data type in isolation from others. We biologically validate that they have a role in cancer and find additional support via retrospective survival analyses of thousands of patients. Our methodology is universal and enables integrative comparisons of diverse molecular data over cells and tissues.
Bad fats in the brain (2019)
Pujol Onofre, Aurora (IDIBELL)view details
Genomic Medicine approach identifies a novel brain disease and its potential treatment. Leukodystrophies are rare inherited disorders that affect the white matter of the brain, the myelin sheath, resulting in a range of severe and often lethal neurological presentations. Several leukodystrophy-associated genes have been identified; however, the etiology of many cases remains unsolved. The use of whole exome sequencing and novel platforms for international data exchange (GeneMatcher) led to the identification of mutations in the endoplasmic reticulum lipid desaturase DEGS1 as the underlying cause of a new ultrarare disease in 19 patients from 13 unrelated families, spread over four continents. The novel disease is called Hypomyelinating Leukodystrophy 18 (HLD18 OMIM: # 618404).
Mutations in DEGS1 caused imbalance of the DEGS1 substrate dihydroceramides, and its product, the ceramides. In a DEGS1 knockdown zebrafish model, treatment with a drug in use for multiple sclerosis, fingolimod, reduced the imbalance between dihydroceramides and ceramides, restored locomotor deficits, and increased the numbers of oligodendrocytes, the cells producing myelin, suggesting this strategy be explored for DEGS1 patients. An international pilot clinical trial for DEGS1 patients is in progress.
The work has been prized as Best Late-Breaking Talk at the International Society for Inherited Errors of Metabolism congress, SSIEM, Amsterdam, September 5th 2019.