Biology subjects

Rottmar, M.

Publications and source records attributed to Rottmar, M..

5 recordsLinked to original sources

bioRxiv2026

A dermal-epidermal junction-inclusive skin model enabled by controllable hydrogel swelling

Tissue engineered skin models are important tools for the in vitro study of physiological and pathophysiological processes as well as the evaluation of therapeutic strategies and the efficacy of pharmaceutical and cosmetic compounds. Replicating the functional anatomy of cutaneous tissue is a crucial aspect in ensuring that observations made using these models are translatable to the actual situation in native skin. However, most contemporary full-thickness skin models neglect the reconstruction of the undulated microtopography of the dermal-epidermal junction (DEJ), which not only contributes to the biological functionality of the skin (e.g. stem cell niches), but also affects tissue mechanics and drug diffusion. Herein, we fabricated bilayer skin models with DEJ-like microtopographies introduced by interfacial wrinkling between a hydrogel and a nanofibrous membrane through a controllable swelling-deswelling approach. The interfacial wrinkles contributed to the structural integrity of the bilayer models. Their formation could be induced in the presence of living cells through mechanical stress-driven buckling instabilities, thus differentiating the process from commonly used pre-patterning techniques. Bilayer models supported the co-culture of human dermal fibroblasts and human epidermal keratinocytes, and the formation of stratified epithelia. Our findings provide a potential alternative method to introduce DEJ-like anatomical features into full-thickness skin tissue models.

bioengineering↗

bioRxiv2026

Decoding molecular programs that define macrophage responses to tumor-derived cues

Tumor-associated macrophages (TAMs) comprise functionally diverse states that can suppress anti-tumor immunity and promote tumor progression, yet the tumor microenvironmental cues and signaling programs that generate these states remain incompletely defined. Here, we systematically stimulate primary human monocyte-derived macrophages with a panel of cytokines and metabolites abundant in the tumor microenvironment (TME), and profile their transcriptomic and phosphoproteomic responses to resolve stimulus-specific molecular programs. We observe that potassium (K+) and adenosine (Ado) stimulation, which accumulate in necrotic tumor cores, downregulate antigen-presentation genes and their master regulator CIITA. K+ stimulation results in the upregulated fibronectin 1 expression, associated with immunosuppressive, metastasis-promoting TAM subsets. Ado induces upregulated expression of tryptophan (Trp) catabolism genes, myeloid checkpoints and metallothioneins (MTs). Although MT-high TAM states have been recurrently observed across tumor single cell RNA sequencing studies, their function remains poorly defined. We show that elevated MT expression in tumor tissue is associated with shorter overall survival. By aligning in vitro transcriptomes with single-cell RNA sequencing (scRNA-seq) signatures from a pan-cancer TAM atlas, we identify significant similarities between several in vitro states and clinically observed TAM populations, with Ado-stimulated macrophages closely resembling a MT-expressing TAM cluster. Overall, this work provides a systematic molecular context linking tumor microenvironmental cues to clinically relevant TAM states and offers a framework for recapitulating their functions in vitro. STATEMENT OF SIGNIFICANCEThis study explores how cytokines and metabolites from the tumor microenvironment shape macrophage molecular phenotypes and lead to the upregulation of clinically relevant marker genes and recapitulation of functional states of interest.

immunology↗

bioRxiv2025

Towards light responsive hydrogel-based valves for flow regulation

Smart hydrogels are promising materials for soft actuators in biomedical applications thanks to their varied responses to external stimuli. Light is a particularly attractive trigger for contactless stimulation of hydrogels that can induce reversible morphological changes without damaging the fragile gels. To meet the varied needs of applications in microfluidics, soft robotics, biomedicine, and other fields, there is significant demand for novel valve designs that are highly tunable, miniaturizable, and respond quickly to stimuli while maintaining their function over many activation cycles. Additionally, it is crucial to develop a more quantitative understanding of the mechanics of valve operation in response to different stimuli, especially when active hydrogels are combined with other materials in multi-component devices. Here, stimuli-responsive valves are fabricated using active hydrogels deformed upon temperature changes and exposure to near-infrared radiation. Gold nanorods (AuNRs) acting as photothermal transducers are embedded inside N-isopropylacrylamide (NIPAM), allowing local morphological changes in response to light with high spatiotemporal control. These changes are described precisely as a function of the valves confinement, aspect ratio, and the parameters of the stimulus using quantitative image analysis, providing novel mechanistic insights. Changing the aspect ratio of the valves and the degree of confinement of the hydrogel causes valves to either open or close during heating and can be used to control the magnitude of their response to different stimuli. These varied morphological changes are due to local, inhomogeneous deformations of the gel. The use of light as a trigger enables local confinement of the valve, reversible opening and closing, and fast response times on the order of seconds. The valves are shown to withstand hydrostatic pressures of up to 18 kPa, providing high potential for biomedical applications where precise pressure control and quick switching between open and closed states is critical. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/686031v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@239b78org.highwire.dtl.DTLVardef@1b40b5corg.highwire.dtl.DTLVardef@155c6eaorg.highwire.dtl.DTLVardef@763dbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Delineation of signaling routes that underlie differences in macrophage phenotypic states

Macrophages represent a major immune cell type in tumor microenvironments, they exist in multiple functional states and are of a strong interest for therapeutic reprogramming. While signaling cascades defining pro-inflammatory macrophages are better characterized, pathways that drive polarization in immunosuppressive macrophages are incompletely mapped. Here, we performed an in-depth characterization of signaling events in primary human macrophages in different functional states using mass spectrometry-based proteomic and phosphoproteomic profiling. Analysis of direct and indirect footprints of kinase activities has suggested PAK2 and PKC kinases as important regulators of in vitro immunosuppressive macrophages (IL-4/IL-13 or IL-10 stimulated). Network integration of these data with the corresesponding transcriptome profiles has further highlighted FOS and NCOR2 as central transcription regulators in immunosuppressive states. Furthermore, we retrieved single cell sequencing datasets for tumors from cancer patients and found that the unbiased signatures identified here through proteomic analysis were able to successfully separate pro-inflammatory macrophage populations in a clinical setting and could thus be used to expand state-specific markers. This study contributes to in-depth multi-omics characterizations of macrophage phenotypic landscapes, which could be valuable for assisting future interventions that therapeutically alter immune cell compartments. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/574349v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1234713org.highwire.dtl.DTLVardef@10f4999org.highwire.dtl.DTLVardef@a8dd60org.highwire.dtl.DTLVardef@5dfb33_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGlobal proteomic characterization of primary human macrophages in different states C_LIO_LIMapping of main signaling events through in-depth data analysis C_LIO_LIPKC and PAK2 kinases are important regulators of immunosuppressive macrophages C_LIO_LIProteomic signatures enable accurate detection of pro-inflammatory macrophages in patient tumors C_LI

bioinformatics↗

bioRxiv2019

Electron microscopy characterization of minerals formed in vitro by human bone cells and vascular smooth muscle cells

Soft tissue mineralization has been found to be a major component of diseases such as aortic valve stenosis and rheumatic heart disease. Cardiovascular mineralization has been suggested to follow mechanisms similar to those of bone formation with several cell culture models been developed over the years to provide mechanistic insights. These cell models have been characterized by a wide range of biochemical and molecular methods, which identified the presence of osteogenic markers and bone-like cells. However, there is a surprisingly small number of studies where the mineral formed in these cell culture models has been characterized by physico-chemical methods, and even fewer studies have compared this mineral to the one produced by bone cells in cultures. Here we investigated the morphology and composition of the minerals formed in cell cultures of vascular smooth muscle cells and bone cells. Electron microscopy and traditional cell mineralization assays were applied, revealing that vascular cells are indeed able to form calcified nodules of elemental composition similar to bone, however with different morphology. Comparison of morphologies of the two minerals to that found in cardiovascular tissue shows that some of tissue calcification resembles the calcified fibers produced by bone cells in vitro. These results suggest that the characterization of the mineral is of utmost importance and its morphology and chemical properties can contribute an important piece of information in the comprehensive analysis of soft tissue mineralization mechanisms, both in in vitro cell culture as well as in clinical samples.

pathology↗