Bernhard L. Bader

Bio: Bernhard L. Bader is an academic researcher from Technische Universität München. The author has contributed to research in topics: Offspring & Adipose tissue. The author has an hindex of 21, co-authored 27 publications receiving 3797 citations. Previous affiliations of Bernhard L. Bader include Max Planck Society.

Rapid leukocyte migration by integrin-independent flowing and squeezing

Abstract: All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus

Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts

Abstract: Id proteins may control cell differentiation by interfering with DNA binding of transcription factors. Here we show that targeted disruption of the dominant negative helix–loop–helix proteins Id1 and Id3 in mice results in premature withdrawal of neuroblasts from the cell cycle and expression of neural-specific differentiation markers. The Id1–Id3 double knockout mice also display vascular malformations in the forebrain and an absence of branching and sprouting of blood vessels into the neuroectoderm. As angiogenesis both in the brain and in tumours requires invasion of avascular tissue by endothelial cells, we examined the Id knockout mice for their ability to support the growth of tumour xenografts. Three different tumours failed to grow and/or metastasize in Id1+/-Id3-/- mice, and any tumour growth present showed poor vascularization and extensive necrosis. Thus, the Id genes are required to maintain the timing of neuronal differentiation in the embryo and invasiveness of the vasculature. Because the Id genes are expressed at very low levels in adults, they make attractive new targets for anti-angiogenic drug design.

Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies

Abstract: Vascular development and maturation are dependent on the interactions of endothelial cell integrins with surrounding extracellular matrix. Previous investigations of the primacy of certain integrins in vascular development have not addressed whether this could also be a secondary effect due to poor embryonic nutrition. Here, we show that the α 5 integrin subunit and fibronectin have critical roles in blood vessel development in mouse embryos and in embryoid bodies (EBs) differentiated from embryonic stem cells (a situation in which there is no nutritional deficit caused by the mutations). In contrast, vascular development in vivo and in vitro is not strongly dependent on α v or β 3 integrin subunits. In mouse embryos lacking α 5 integrin, greatly distended blood vessels are seen in the vitelline yolk sac and in the embryo itself. Additionally, overall blood vessel pattern complexity is reduced in α 5 -null tissues. This defective vascular phenotype is correlated with a decrease in the ligand for α 5 integrin, fibronectin (FN), in the endothelial basement membranes. A striking and significant reduction in early capillary plexus formation and maturation was apparent in EBs formed from embryonic stem cells lacking α 5 integrin or FN compared with wild-type EBs or EBs lacking α v or β 3 integrin subunits. Vessel phenotype could be partially restored to FN-null EBs by the addition of whole FN to the culture system. These findings confirm a clear role for α 5 and FN in early blood vessel development not dependent on embryo nutrition or α v or β 3 integrin subunits. Thus, successful early vasculogenesis and angiogenesis require α 5 -FN interactions.

Compound genetic ablation of nidogen 1 and 2 causes basement membrane defects and perinatal lethality in mice.

Abstract: Nidogen 1 and 2 are basement membrane glycoproteins, and previous biochemical and functional studies indicate that they may play a crucial role in basement membrane assembly. While they show a divergent expression pattern in certain adult tissues, both have a similar distribution during development. Gene knockout studies in mice demonstrated that the loss of either isoform has no effect on basement membrane formation and organ development, suggesting complementary functions. Here, we show that this is indeed the case. Deficiency of both nidogens in mice resulted in perinatal lethality. Nidogen 1 and 2 do not appear to be crucial in establishing tissue architecture during organ development; instead, they are essential for late stages of lung development and for maintenance and/or integrity of cardiac tissue. These organ defects are not compatible with postnatal survival. Ultrastructural analysis suggests that the phenotypes directly result from basement membrane changes. However, despite the ubiquitous presence of nidogens in basement membranes, defects do not occur in all tissues or in all basement membranes, suggesting a varying spectrum of roles for nidogens in the basement membrane.

Mechanisms of angiogenesis and arteriogenesis.

Abstract: Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.

VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche

Abstract: The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

Interventions for preventing obesity in children

Abstract: The current evidence suggests that many diet and exercise interventions to prevent obesity in children are not effective in preventing weight gain, but can be effective in promoting a healthy diet and increased physical activity levels.Being very overweight (obese) can cause health, psychological and social problems for children. Children who are obese are more likely to have weight and health problems as adults. Programmes designed to prevent obesity focus on modifying one or more of the factors considered to promote obesity.This review included 22 studies that tested a variety of intervention programmes, which involved increased physical activity and dietary changes, singly or in combination. Participants were under 18 and living in Asia, South America, Europe or North America. There is not enough evidence from trials to prove that any one particular programme can prevent obesity in children, although comprehensive strategies to address dietary and physical activity change, together with psycho-social support and environmental change may help. There was a trend for newer interventions to involve their respective communities and to include evaluations.Future research might usefully assess changes made on behalf of entire populations, such as improvements in the types of foods available at schools and in the availability of safe places to run and play, and should assess health effects and costs over several years.The programmes in this review used different strategies to prevent obesity so direct comparisons were difficult. Also, the duration of the studies ranged from 12 weeks to three years, but most lasted less than a year.

The extracellular matrix: A dynamic niche in cancer progression

Abstract: The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.