BIH Paper of the Month

The BIH Paper of the Month is awarded by the BIH Board of Directors to honor a special publication achievement from the joint research space of Charité and MDC. The Paper of the Month is sponsored by the Stiftung Charité as part of its Johanna Quandt Private Excellence Initiative. The prize is awarded at the beginning of each month for a paper published the month before last (i.e. in March a paper will be honored that was published in January). The date of publication that counts here is the date of public accessibility (online and/or print), not an “advanced publication” of an author manuscript that has been accepted for publication. The award is endowed with €500 and goes to the group leader with BIH affiliation.

Publications that can be considered for the award include all those found in a PubMed search in the relevant month for articles with a direct BIH affiliation (affiliation through corporate bodies of the BIH alone is not sufficient).

Publications can also be proposed to the BIH per e-mail at any time.

Criteria for the award

  • Mention of BIH affiliation

  • Fit with BIH strategy
    - Contribution to the research/diagnosis/therapy of progressive diseases
    - Transfer between basic and clinical research
    - Transfer between research and commercial application
    - Use of BIH infrastructures
  • Originality of the work

  • Quality assurance measures in the writing and publication of the paper (e.g. open access/open data publications, use of electronic laboratory journals, transparent documentation of study planning and implementation, publication of negative and neutral results, replication studies, etc.)

  • Participation of
    - Young researchers
    - Various research disciplines
    - International authors

  • Gender balance

JANUARY – Interleukin-22 protects intestinal stem cells against genotoxic stress

Andreas Diefenbach and his team received the Paper of the Month award for January 2019. Press release: How the immune system protects us against bowel cancer

Gronke K, Hernández PP, Zimmermann J, Klose CSN, Kofoed-Branzk M, Guendel F, Witkowski M, Tizian C, Amann L, Schumacher F, Glatt H, Triantafyllopoulou A, Diefenbach A. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 2019 Feb;566(7743):249-253. doi: 10.1038/s41586-019-0899-7. Epub 2019 Jan 30.


Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR), and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.


DECEMBER – The Short-Chain Fatty Acid Propionate Protects from Hypertensive Cardiovascular Damage

In December Nicola Wilck and his team received the Paper of the Month award. Read the interview

Bartolomaeus H, Balogh A, Yakoub M, Homann S, Markó L, Höges S, Tsvetkov D, Krannich A, Wundersitz S, Avery EG, Haase N, Kräker K, Hering L, Maase M, Kusche-Vihrog K, Grandoch M, Fielitz J, Kempa S, Gollasch M, Zhumadilov Z, Kozhakhmetov S, Kushugulova A, Eckardt KU, Dechend R, Rump LC, Forslund SK, Müller DN, Stegbauer J, Wilck N. The Short-Chain Fatty Acid Propionate Protects from Hypertensive Cardiovascular Damage. Circulation. 2018 Dec 4. doi: 10.1161/CIRCULATIONAHA.118.036652.


Background: Arterial hypertension and its organ sequelae show characteristics of T cell mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study targeting interleukin-1β demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFA) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in two different mouse models of hypertensive cardiovascular damage.

Methods: To investigate the effect of SCFA on hypertensive cardiac damage and atherosclerosis, wild-type NMRI (WT) or ApoE-/- deficient mice received propionate (200mM) or control in the drinking water. To induce hypertension, WT mice were infused with Angiotensin (Ang)II (1.44mg/kg/d s.c.) for 14 days. To accelerate the development of atherosclerosis, ApoE-/- mice were infused with AngII (0.72mg/kg/d s.c.) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell (Treg) depletion using PC61 antibody was used to examine the mode of action of propionate.

Results: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated AngII-infused WT mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated ApoE-/-. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in WT mice. Cardioprotective effects of propionate were abrogated in Treg-depleted AngII-infused mice, suggesting the effect is Treg-dependent.

Conclusions: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial non-pharmacological preventive strategy for patients with hypertensive cardiovascular disease.

NOVEMBER – An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance

In November Knut Mai, coordinator Clinical Research Unit (CRU), and his team received the Paper of the Month award. Read the interview

Mai K, Li L, Wiegand S, Brachs M, Leupelt V, Ernert A, Kühnen P, Hübner N, Robinson P, Chen W, Krude H, Spranger J. An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance. Diabetes. 2019 Jan;68(1):57-65. doi: 10.2337/db18-0440. Epub 2018 Nov 2.


Lifestyle-based weight loss interventions frequently demonstrate long-term inefficiency and weight regain. Identification of underlying mechanisms and predictors to identify subjects who will benefit from lifestyle-based weight loss strategies is urgently required. We analyzed 143 adults of the randomized Maintain trial (Maintain-Adults) after intended weight loss to identify mechanisms contributing to the regulation of body weight maintenance. Unbiased RNA sequencing of adipose and skeletal muscle biopsies revealed fatty acid metabolism as a key pathway modified by weight loss. Variability of key enzymes of this pathway, estimates of substrate oxidation, and specific serum acylcarnitine (AC) species, representing a systemic snapshot of in vivo substrate flux, predicted body weight maintenance (defined as continuous or dichotomized [< or ≥3% weight regain] variable) 18 months after intended weight loss in the entire cohort. Key results were confirmed in a similar randomized controlled trial in 137 children and adolescents (Maintain-Children), which investigated the same paradigm in a pediatric cohort. These data suggest that adaption of lipid utilization in response to negative energy balance contributes to subsequent weight maintenance. Particularly a functional role for circulating ACs, which have been suggested to reflect intracellular substrate utilization, as mediators between peripheral energy stores and control of long-term energy homeostasis was indicated.

OCTOBER – High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population

In October Dimitrios L. Wagner and his team received the Paper of the Month award. Read the interview

Wagner DL, Amini L, Wendering DJ, Burkhardt LM, Akyüz L, Reinke P, Volk HD, Schmueck-Henneresse M. High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population. Nat Med. 2018 Oct 29. doi: 10.1038/s41591-018-0204-6


The discovery of the highly efficient site-specific nuclease system CRISPR-Cas9 from Streptococcus pyogenes has galvanized the field of gene therapy. The immunogenicity of Cas9 nuclease has been demonstrated in mice. Preexisting immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear whether it induces a T cell memory against the Cas9 nuclease. Here, we show the presence of a preexisting ubiquitous effector T cell response directed toward the most widely used Cas9 homolog from S. pyogenes (SpCas9) within healthy humans. We characterize SpCas9-reactive T cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity, and lineage determination. In-depth analysis of SpCas9-reactive T cells reveals a high frequency of SpCas9-reactive regulatory T cells that can mitigate SpCas9-reactive effector T cell proliferation and function in vitro. Our results shed light on T cell-mediated immunity toward CRISPR-associated nucleases and offer a possible solution to overcome the problem of preexisting immunity.

SEPTEMBER – Machine learning for real-time prediction of complications in critical care: a retrospective study

In September, Alexander Meyer and his team received the Paper of the Month award.

Meyer A, Zverinski D, Pfahringer B, Kempfert J, Kuehne T, Sündermann SH, Stamm C, Hofmann T, Falk V, Eickhoff C. Machine learning for real-time prediction of complications in critical care: a retrospective study.Lancet Respir Med. 2018 Sep 28. pii: S2213-2600(18)30300-X. doi: 10.1016/S2213-2600(18)30300-X.


The large amount of clinical signals in intensive care units can easily overwhelm health-care personnel and can lead to treatment delays, suboptimal care, or clinical errors. The aim of this study was to apply deep machine learning methods to predict severe complications during critical care in real time after cardiothoracic surgery.

We used deep learning methods (recurrent neural networks) to predict several severe complications (mortality, renal failure with a need for renal replacement therapy, and postoperative bleeding leading to operative revision) in post cardiosurgical care in real time. Adult patients who underwent major open heart surgery from Jan 1, 2000, to Dec 31, 2016, in a German tertiary care centre for cardiovascular diseases formed the main derivation dataset. We measured the accuracy and timeliness of the deep learning model's forecasts and compared predictive quality to that of established standard-of-care clinical reference tools (clinical rule for postoperative bleeding, Simplified Acute Physiology Score II for mortality, and the Kidney Disease: Improving Global Outcomes staging criteria for acute renal failure) using positive predictive value (PPV), negative predictive value, sensitivity, specificity, area under the curve (AUC), and the F1 measure (which computes a harmonic mean of sensitivity and PPV). Results were externally retrospectively validated with 5898 cases from the published MIMIC-III dataset.

Of 47 559 intensive care admissions (corresponding to 42 007 patients), we included 11 492 (corresponding to 9269 patients). The deep learning models yielded accurate predictions with the following PPV and sensitivity scores: PPV 0·90 and sensitivity 0·85 for mortality, 0·87 and 0·94 for renal failure, and 0·84 and 0·74 for bleeding. The predictions significantly outperformed the standard clinical reference tools, improving the absolute complication prediction AUC by 0·29 (95% CI 0·23-0·35) for bleeding, by 0·24 (0·19-0·29) for mortality, and by 0·24 (0·13-0·35) for renal failure (p<0·0001 for all three analyses). The deep learning methods showed accurate predictions immediately after patient admission to the intensive care unit. We also observed an increase in performance in our validation cohort when the machine learning approach was tested against clinical reference tools, with absolute improvements in AUC of 0·09 (95% CI 0·03-0·15; p=0·0026) for bleeding, of 0·18 (0·07-0·29; p=0·0013) for mortality, and of 0·25 (0·18-0·32; p<0·0001) for renal failure.

The observed improvements in prediction for all three investigated clinical outcomes have the potential to improve critical care. These findings are noteworthy in that they use routinely collected clinical data exclusively, without the need for any manual processing. The deep machine learning method showed AUC scores that significantly surpass those of clinical reference tools, especially soon after admission. Taken together, these properties are encouraging for prospective deployment in critical care settings to direct the staff's attention towards patients who are most at risk.

AUGUST – Exon Skipping in a Dysf-Missense Mutant Mouse Model

In August Verena Schöwel and her team received the Paper of the Month award. Read interview

Jakub Malcher, Leonie Heidt , Aurélie Goyenvalle , Helena Escobar , Andreas Marg, Cyriaque Beley , Rachid Benchaouir, Michael Bader, SimoneSpuler, Luis García, Verena Schöwel. Exon Skipping in a Dysf-Missense Mutant Mouse Model. Mol Ther Nucleic Acids. 2018 Dec 7; 13: 198–207. Published online 2018 Aug 22. doi: 10.1016/j.omtn.2018.08.013


Limb girdle muscular dystrophy 2B (LGMD2B) is without treatment and caused by mutations in the dysferlin gene (DYSF). One-third is missense mutations leading to dysferlin aggregation and amyloid formation, in addition to defects in sarcolemmal repair and progressive muscle wasting. Dysferlin-null mouse models do not allow study of the consequences of missense mutations. We generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. We chose U7 small nuclear RNA (snRNA)-based splice switching to demonstrate a possible exon-skipping strategy in this new animal model. We show that Dysf exons 37 and 38 can successfully be skipped in vivo. Overall, the MMex38 mouse model provides an ideal tool for preclinical development of treatment strategies for dysferlinopathy.

JULY – Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes

In July, BIH Professor Ulf Landmesser and his team received the Paper of the Month award. Read the interview

Haghikia A, Li XS, Liman TG, Bledau N, Schmidt D, Zimmermann F, Kränkel N, Widera C, Sonnenschein K, Haghikia A, Weissenborn K, Fraccarollo D, Heimesaat MM, Bauersachs J, Wang Z, Zhu W, Bavendiek U, Hazen SL, Endres M, Landmesser U. Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. Arterioscler Thromb Vasc Biol. 2018 Jul 5. pii: ATVBAHA.118.311023. doi: 10.1161/ATVBAHA.118.311023.



Gut microbiota-dependent metabolites, in particular trimethylamine N-oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied.


In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes (r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2±0.5×103 per mL versus ctr.: 6.5±0.5×103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+ABS: 5.4±0.7×103 per mL; P<0.001 versus choline).

The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO-related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels.

JUNE – SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling

In June, Ioana Alesutan and her team were awarded the Paper of the Month. Read interview

Voelkl J, Luong TT, Tuffaha R, Musculus K, Auer T, Lian X, Daniel C, Zickler D, Boehme B, Sacherer M, Metzler B, Kuhl D, Gollasch M, Amann K, Müller DN, Pieske B, Lang F, Alesutan I. SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling. J Clin Invest. 2018 Jul 2;128(7):3024-3040. doi: 10.1172/JCI96477.


edial vascular calcification, associated with enhanced mortality in chronic kidney disease (CKD), is fostered by osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Here, we describe that serum- and glucocorticoid-inducible kinase 1 (SGK1) was upregulated in VSMCs under calcifying conditions. In primary human aortic VSMCs, overexpression of constitutively active SGK1S422D, but not inactive SGK1K127N, upregulated osteo-/chondrogenic marker expression and activity, effects pointing to increased osteo-/chondrogenic transdifferentiation. SGK1S422D induced nuclear translocation and increased transcriptional activity of NF-κB. Silencing or pharmacological inhibition of IKK abrogated the osteoinductive effects of SGK1S422D. Genetic deficiency, silencing, and pharmacological inhibition of SGK1 dissipated phosphate-induced calcification and osteo-/chondrogenic transdifferentiation of VSMCs. Aortic calcification, stiffness, and osteo-/chondrogenic transdifferentiation in mice following cholecalciferol overload were strongly reduced by genetic knockout or pharmacological inhibition of Sgk1 by EMD638683. Similarly, Sgk1 deficiency blunted vascular calcification in apolipoprotein E-deficient mice after subtotal nephrectomy. Treatment of human aortic smooth muscle cells with serum from uremic patients induced osteo-/chondrogenic transdifferentiation, effects ameliorated by EMD638683. These observations identified SGK1 as a key regulator of vascular calcification. SGK1 promoted vascular calcification, at least partly, via NF-κB activation. Inhibition of SGK1 may, thus, reduce the burden of vascular calcification in CKD.

MAY – Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes

In May Clinician Scientist Julia Sbierski-Kind and her Team were awarded with the Paper of the Month. Read the interview

Sbierski-Kind J, Kath J, Brachs S, Streitz M, von Herrath MG, Kühl AA, Schmidt-Bleek K, Mai K, Spranger J, Volk HD. Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes. Front Immunol. 2018; 9: 1069. Published online 2018 May 28. doi:  10.3389/fimmu.2018.01069


Obesity is associated with adipose tissue inflammation, insulin resistance, and the development of type 2 diabetes (T2D). However, our knowledge is mostly based on conventional murine models and promising preclinical studies rarely translated into successful therapies. There is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet (HFD). We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so-called “antigen exposed” (AE) conditions. Surprisingly, AE mice fed a HFD maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. By contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of HFD AE mice accompanied by the development of non-alcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for T2D patients.

APRIL – Diabetes mellitus in pregnancy leads to growth restriction and epigenetic modification of the Srebf2 gene in rat fetuses

In April, Clinician Scientist Michaela Golić and Ralf Dechend from the TRG Fetal programming of cardiometabolic disease received the Paper of the Month award. Read the interview

Golic, M.Stojanovska, V.Bendix, I.Wehner, A.Herse, F.Haase, N.Kräker, K.Fischer, C.Alenina, N.Bader, M.Schütte, T.;  Schuchardt, M.van der Giet, M.Henrich, W.Muller, D.N.Felderhoff-Müser, U.Scherjon, S.Plösch, T.Dechend, R. Diabetes mellitus in pregnancy leads to growth restriction and epigenetic modification of the Srebf2 gene in rat fetuses. Hypertension. 2018;71:911-920.


Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.


MARCH – Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression

In March, Holger Gerhardt, BIH Professor for Experimental Cardiovascular Research, receives the BIH Paper of the Month award. Read interview

Vion AC, Alt S, Klaus-Bergmann A, Szymborska A, Zheng T, Perovic T, Hammoutene A, Oliveira MB, Bartels-Klein E, Hollfinger I, Rautou PE, Bernabeu MO, Gerhardt H. Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. J Cell Biol. 201706151. DOI: 10.1083/jcb.201706151


Blood flow shapes vascular networks by orchestrating endothelial cell behavior and function. How endothelial cells read and interpret flow-derived signals is poorly understood. Here, we show that endothelial cells in the developing mouse retina form and use luminal primary cilia to stabilize vessel connections selectively in parts of the remodeling vascular plexus experiencing low and intermediate shear stress. Inducible genetic deletion of the essential cilia component intraflagellar transport protein 88 (IFT88) in endothelial cells caused premature and random vessel regression without affecting proliferation, cell cycle progression, or apoptosis. IFT88 mutant cells lacking primary cilia displayed reduced polarization against blood flow, selectively at low and intermediate flow levels, and have a stronger migratory behavior. Molecularly, we identify that primary cilia endow endothelial cells with strongly enhanced sensitivity to bone morphogenic protein 9 (BMP9), selectively under low flow. We propose that BMP9 signaling cooperates with the primary cilia at low flow to keep immature vessels open before high shear stress–mediated remodeling.


FEBRUARY – CLCN2 chloride channel mutations in familial hyperaldosteronism type II

In February Ute Scholl receives the Paper of the Month award. Read the interview

Ute I. Scholl, Gabriel Stölting, Julia Schewe, Anne Thiel, Hua Tan, Carol Nelson-Williams, Alfred A. Vichot, Sheng Chih Jin, Erin Loring, Verena Untiet, Taekyeong Yoo, Jungmin Choi, Shengxin Xu, Aihua Wu, Marieluise Kirchner, Philipp Mertins, Lars C. Rump, Ali Mirza Onder, Cory Gamble, Daniel McKenney, Robert W. Lash, Deborah P. Jones, Gary Chune, Priscila Gagliardi, Murim Choi, Richard Gordon, Michael Stowasser, Christoph Fahlke & Richard P. Lifton. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics 2018. DOI: 10.1038/s41588-018-0048-5


Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.


JANUARY – Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma

The Paper of the Month went to Viktor Arnhold and Patrick Hundsdörfer in January. Read the interview

Viktor Arnhold, Karin Schmelz, Jutta Proba, Annika Winkler, Jasmin Wünschel, Joern Toedling, Hedwig E. Deubzer, Annette Künkele, Angelika Eggert, Johannes H. Schulte1 and Patrick Hundsdoerfer. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget. 2018; 9:2304-2319.


Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity.


DECEMBER '18 – A Transgenic Dual-Luciferase Reporter Mouse for Longitudinal and Functional Monitoring of T Cells In Vivo

In December, the BIH Johanna Quandt Professor Il-Kang Na and Martin Szyska were awarded the Paper of the Month. Read the interview

Martin Szyska, Stefanie Herda, Stefanie Althoff, Andreas Heimann, Josefine Russ, Daniele D'Abundo, Tra My Dang, Isabell Durieux, Bernd Dörken, Thomas Blankenstein and Il-Kang Na. A Transgenic Dual-Luciferase Reporter Mouse for Longitudinal and Functional Monitoring of T Cells In Vivo. Cancer Immunol Res. 2018 Jan;6(1):110-120. doi: 10.1158/2326-6066.CIR-17-0256. Epub 2017 Dec 19


Adoptive T-cell therapy (ATT) efficacy is limited when targeting large solid tumors. The evaluation of ATT outcomes using accessory treatment would greatly benefit from an in vivo monitoring tool, allowing the detection of functional parameters of transferred T cells. Here, we generated transgenic bioluminescence imaging of T cells (BLITC) mice expressing an NFAT-dependent click-beetle luciferase and a constitutive Renilla luciferase, which supports concomitant in vivo analysis of migration and activation of T cells. Rapid transferability of our system to preestablished tumor models was demonstrated in the SV40-large T antigen model via both crossbreeding of BLITC mice into a T-cell receptor (TCR)-transgenic background and TCR transduction of BLITC T cells. We observed rapid tumor infiltration of BLITC CD8+ T cells followed by a burst-like activation that mirrored rejection kinetics. Using the BLITC reporter in the clinically relevant H-Y model, we performed female to male transfers and detected H-Y-specific alloreactivity (graft-versus-host disease) in vivo In an H-Y solid tumor model, we found migration of adoptively transferred H-Y TCR-transgenic CD4+ T cells into the tumor, marked by transient activation. This suggests a rapid inactivation of infiltrating T cells by the tumor microenvironment, as confirmed by their expression of inhibitory receptors. In summary, the BLITC reporter system facilitates analysis of therapeutic parameters for ATT, is rapidly transferable to models of interest not restricted to tumor research, and is suitable for rapid screening of TCR clones for tumor rejection kinetics, as well as off-target effects.


NOVEMBER '18 (2) – Salt-responsive gut commensal modulates TH17 axis and disease

There was no award in October, but two papers were awarded in November.

In November, Dominik N. Müller and Nicola Wilck his team received the Paper of the Month award. Read about the project in this MDC Insights article Gut bacteria are sensitive to salt.

Nicola Wilck, Mariana G. Matus, Sean M. Kearney, Scott W. Olesen, Kristoffer Forslund, Hendrik Bartolomaeus, Stefanie Haase, Anja Mähler, András Balogh, Lajos Markó, Olga Vvedenskaya, Friedrich H. Kleiner, Dmitry Tsvetkov, Lars Klug, Paul I. Costea, Shinichi Sunagawa, Lisa Maier, Natalia Rakova, Valentin Schatz, Patrick Neubert, Christian Frätzer, Alexander Krannich, Maik Gollasch, Diana A. Grohme, Beatriz F. Côrte-Real, Roman G. Gerlach, Marijana Basic, Athanasios Typas, Chuan Wu, Jens M. Titze, Jonathan Jantsch, Michael Boschmann, Ralf Dechend, Markus Kleinewietfeld, Stefan Kempa, Peer Bork, Ralf A. Linker, Eric J. Alm & Dominik N. Müller. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589. 30. November 2017.

You can download the publication here.


A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.


NOVEMBER '18 (1) – Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

There was no award in October, but two papers were awarded in November.

In November, BIH Charité Clinician Scientist Anton G. Henssen and his team received the Paper of the Month award. Read the interview

Anton G. Henssen, Casie Reed, Eileen Jiang1, Heathcliff Dorado Garcia, Jennifer von Stebut, Ian C. MacArthur, Patrick Hundsdoerfer, Jun Hyun Kim, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Neil J. Ganem, Filemon Dela Cruz, Andrew L. Kung, Johannes H. Schulte, John H. Petrini and Alex Kentsis. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Science Translational Medicine. 01 Nov 2017. Vol. 9, Issue 414. DOI: 10.1126/scitranslmed.aam9078 

The publication can be downloaded here.


Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity–deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G1-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.


SEPTEMBER '18 – Unbiased identification of T cell receptors targeting immunodominant peptide-MHC complexes for T cell receptor immunotherapy

In September Wolfgang Uckert, Felix Lorenz and the team received the Paper of the Month award. Read the interview

Lorenz FKM, Ellinger C, Kieback E, Wilde S, Lietz M, Schendel DJ, Uckert W. Unbiased identification of T cell receptors targeting immunodominant peptide-MHC complexes for T cell receptor immunotherapy. Hum Gene Ther. 2017 Sep 26. doi: 10.1089/hum.2017.122. 

You can download the publication here.


T cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01), and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.


AUGUST '18 – A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice

In August, Wolfgang Böhmerle, Matthias Endres and Petra Hühnchen received the Paper of the Month award. Read the interview

Huehnchen P, Boehmerle W, Springer A, Freyer D, Endres M. A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice. Transl Psychiatry. 2017 Aug 1;7(8):e1185. doi: 10.1038/tp.2017.149.

You can download the publication here.


Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.


JUNE '18 – Phospho-AXL is widely expressed in glioblastoma and associated with significant shorter overall survival

In June, Josefine Radke, Julia Onken and the team received the Paper of the Month award for the publication on a pathway that plays an important role in the development of malignant gliomas. Read the interview

Onken J, Vajkoczy P, Torka R, Hempt C, Patsouris V, Heppner FL, Radke J. Phospho-AXL is widely expressed in glioblastoma and associated with significant shorter overall survival. Oncotarget. 2017 Jun 13. doi: 10.18632/oncotarget.18468.

You can download the publication here.


Receptor tyrosine kinase AXL (RTK-AXL) is regarded as a suitable target in glioblastoma (GBM) therapy. Since AXL kinase inhibitors are about to get approval for clinical use, patients with a potential benefit from therapy targeting AXL need to be identified. We therefore assessed the expression pattern of Phospho-AXL (P-AXL), the biologically active form of AXL, in 90 patients with newly diagnosed GBM, which was found to be detectable in 67 patients (corresponding to 74%). We identified three main P-AXL expression patterns: i) exclusively in the tumor vasculature (13%), ii) in areas of hypercellularity (35%), or iii) both, in the tumor vasculature and in hypercellular areas of the tumor tissue (52%). Pattern iii) is associated with significant decrease in overall survival (Hazard ratio 2.349, 95% confidence interval 1.069 to 5.162, *p=0.03). Our data suggest that P-AXL may serve as a therapeutic target in the majority of GBM patients.


MAY '18 – An immediate-late gene expression module decodes ERK signal duration

In May, Nils Blüthgen and his team received the Paper of the Month for their Open Access publication, in which they investigated the ERK signaling path using mathematical modelling. The publication resulted from BIH funding for the the TRG project "Systems Medicine of BRAF-Driven Malignancies". Read the interview

Uhlitz F, Sieber A, Wyler E, Fritsche-Guenther R, Meisig J, Landthaler M, Klinger B, Blüthgen N. An immediate-late gene expression module decodes ERK signal duration. Mol Syst Biol. 2017 May 3;13(5):928. doi: 10.15252/msb.20177554.

You can download the publication here.


The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function. We find that mRNA longevity enables these ILGs to respond late and thus translate ERK signal duration into response amplitude. Despite their late response, their GC-rich promoter structure suggested and metabolic labelling with 4SU confirmed that transcription of ILGs is induced immediately. A comparative analysis shows that the principle of duration decoding is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Altogether, our findings suggest that ILGs function as a gene expression module to decode ERK signal duration.


APRIL '18 – Tumour ischaemia by interferon-γ resembles physiological blood vessel regression

For their work on the signaling molecule interferon-gamma in cancer development, Thomas Blankenstein and Thomas Kammertoens were awarded with the Paper of the Month 'April'. The work provides evidence for improved T cell therapy against solid cancer deaths. Read the interview

Thomas Kammertoens, Christian Friese, Ainhoa Arina, Christian Idel, Dana Briesemeister, Michael Rothe, Andranik Ivanov, Anna Szymborska, Giannino Patone, Severine Kunz, Daniel Sommermeyer,    Boris Engels, Matthias Leisegang, Ana Textor, Hans Joerg Fehling, Marcus Fruttiger, Michael Lohoff, Andreas Herrmann, Hua Yu, Ralph Weichselbaum, Wolfgang Uckert, Norbert Hübner, Holger Gerhardt, Dieter Beule, Hans Schreiber, Thomas Blankenstein. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature 545, 98–102 (04 May 2017). doi: 10.1038/nature22311 

You can download the publication here.


The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ–GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.


MARCH '18 – Complex multi-enhancer contacts captured by genome architecture mapping

Ana Pombo and her team present a new method in Nature that allows mapping of the three-dimensional topography of the genome. For this, Pombo receives the Paper of the Month 'March'.

Beagrie RA, Scialdone A, Schueler M, Kraemer DC, Chotalia M, Xie SQ, Barbieri M, de Santiago I, Lavitas LM, Branco MR, Fraser J, Dostie J, Game L, Dillon N, Edwards PA, Nicodemi M, Pombo A. Complex multi-enhancer contacts captured by genome architecture mapping. Nature. 2017 Mar 23;543(7646):519-524. doi: 10.1038/nature21411. Epub 2017 Mar 8.

You can download the publication here.


The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.


FEBRUARY '18 – Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans

BIH Charité Clinical Scientist Benjamin Strücker and his team were awarded with the BIH Paper of the Month 'February'. In the open access publication Strücker presents a method by which it is possible to engineer an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. In further tests, the scientists were able to demonstrate that the Langerhans islands were functional and able to produce insulin.

H. Napierala, K.-H. Hillebrandt, N. Haep, P. Tang, M. Tintemann, J. Gassner, M. Noesser, H. Everwien, N. Seiffert, M. Kluge, E. Teegen, D. Polenz, S. Lippert, D. Geisel, A. Reutzel Selke, N. Raschzok, A. Andreou, J. Pratschke, I. M. Sauer & B. Struecker. Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. Scientific Reports 7. Article number: 41777 (2017) doi:10.1038/srep41777

You can download the publication here


Decellularization of pancreata and repopulation of these non-immunogenic matrices with islets and endothelial cells could provide transplantable, endocrine Neo- Pancreata. In this study, rat pancreata were perfusion decellularized and repopulated with intact islets, comparing three perfusion routes (Artery, Portal Vein, Pancreatic Duct). Decellularization effectively removed all cellular components but conserved the pancreas specific extracellular matrix. Digital subtraction angiography of the matrices showed a conserved integrity of the decellularized vascular system but a contrast emersion into the parenchyma via the decellularized pancreatic duct. Islets infused via the pancreatic duct leaked from the ductular system into the peri-ductular decellularized space despite their magnitude. TUNEL staining and Glucose stimulated insulin secretion revealed that islets were viable and functional after the process. We present the first available protocol for perfusion decellularization of rat pancreata via three different perfusion routes. Furthermore, we provide first proof-of-concept for the repopulation of the decellularized rat pancreata with functional islets of Langerhans. The presented technique can serve as a bioengineering platform to generate implantable and functional endocrine Neo-Pancreata.


JANUARY '18 – CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development

At the beginning of March, Angela M. Kaindl from the Institute of Cell Biology and Neurobiology of the Charité was awarded the BIH Paper of the Month. The publication “CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development” was published in Stem Cell Reports under open access conditions with a total of only five authors and a high proportion of BIH affiliates. 

Kaindl has shown in the past that mutations of the CDK5RAP2 gene lead to microcephaly. This paper shows for the first time that the ubiquitously expressed Cdk5rap2 is also required to maintain germ cells during embryonic development. Certain genetic mutations in CDK5RAP2 lead to mitotic delay in germ cells, which is connected to the large-scale death of germ cell derivatives and sterility in male mice. Identifying the mechanisms that cause this death will enhance our understanding of the development of microcephaly and could open up new approaches to the diagnosis of this and other genetic diseases.

Zaqout S, Bessa P, Krämer N, Stoltenburg-Didinger G, Kaindl AM. CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development. Stem Cell Reports. 2017 Jan 31. pii: S2213-6711(17)30017-6. doi: 10.1016/j.stemcr.2017.01.002

Since the publication was published under Open Access conditions, it is freely available. Download here


Gene products linked to microcephaly have been studied foremost for their role in brain development, while their function in the development of other organs has been largely neglected. Here, we report the critical role of Cdk5rap2 in maintaining the germ cell pool during embryonic development. We highlight that infertility in Cdk5rap2 mutant mice is secondary to a lack of spermatogenic cells in adult mice as a result of an early developmental defect in the germ cells through mitotic delay, prolonged cell cycle, and apoptosis.