Open Research Projects, Research

Multi-modal spatial characterization of fibrovascular skin niches in health and disease

Prinicipal Investigator

Prof. Dr. Anja Hauser
Dr. Elise Siegert

Scientific interest within the context of the graduate college:

We are interested in the interaction of endothelial cells and their mesenchymal neighboring cells with immune cells in perivascular tissue areas called fibrovascular niches. These represent crucial strategic sites for resident immune cells regulating tissue homeostasis and maintain structural and functional integrity of blood vessels in health and disease. Factors disturbing structural and functional integrity of fibrovascular niches are associated with pre-mature aging and irreversible organ damage. However, the cellular interplay and molecular basis of those processes are not well understood.

Project description:

Located at the interface between the blood circulation and tissue, fibrovascular niches are strategically positioned to transmit information about systemic conditions to tissues (Pascual-Reguant et al., 2024). This exposition to systemic changes makes them a starting point for certain pathologies, for example tissue fibrosis, as we recently demonstrated (Mothes et al., 2023). Advanced imaging technologies allow us to characterize tissue composition at a cellular and molecular level in various modalities, detecting protein as well as RNA in tissue sections. Using those technologies, we aim to better understand fibrovascular niche functions in vascular health, physiological neovascularization and wound healing as well as in autoimmune rheumatic diseases.

We hypothesize that the spatial organization of various cellular compartments (immune cells, endothelial and mesenchymal cells) in fibrovascular niches is a crucial component of vascular integrity and impacts on functions of the skin in health and disease. We know from previous studies on wound healing that the interaction between macrophages and fibroblasts is a key component in determining the differential functional states of wound healing (Adler et al., 2020). Their reciprocal activation is crucial for scar maturation and results in an upregulation of genes related to epithelial-to-mesenchymal transition and angiogenesis in fibroblasts (Setten et al., 2022).

We will compare cellular composition, cell-cell interactions and molecular pathways under physiological conditions, in physiological wound healing and pathological scaring in the context of the fibrotic autoimmune disease systemic sclerosis; the latter is characterized by diffuse fibrosis and vascular anomalies in skin, joints and organs such as gastrointestinal tract, heart, lungs and kidneys. Whilst disease mechanisms at the tissue level in systemic sclerosis are still incompletely understood, B cell depletion has recently led to many promising therapeutic outcomes (Auth et al., 2025; Siegert et al., 2025).

Aim 1: Determining role of the different cellular components in fibrovascular niche in physiological homeostasis and physiological wound healing, comparison to pathological states such as early systemic sclerosis. We will collect punch biopsy skin samples from healthy controls and from fibrotic skin from systemic sclerosis patients (disease duration of less than two years as defined by onset of first non-Raynaud symptom). We will use spatial transcriptomics for molecular tissue profiling at sub-cellular resolution and map it to the cellular and extra-cellular structures identified using multi-epitope ligand cartography. This will allow is to spatially map cellular and molecular changes occurring during pathologies in fibrovascular niches and identify potential new therapeutic targets.

Aim 2: Identifying cellular changes in the fibrovascular niche following plasma cell depleting therapy with teclistamab, a bispecific antibody against BCMA / CD3, in systemic sclerosis. Our preliminary data show that treatment with subcutaneous teclistamab injections is highly effective in reducing skin fibrosis, resolving inflammation and promoting neoangiogenesis in systemic sclerosis skin (Siegert et al., 2025). We will collect 4 mm punch biopsies skin samples from patients undergoing treatment with teclistamab at baseline and at week 12 after treatment. We will perform untargeted spatial transcriptomics to identify target genes and pathways which we will validate by multiplex immunofluorescence histology. This approach will enable us to identify how the cellular alterations of the fibrovascular niche caused by the B lineage-depleting therapy translate into structural and functional alterations of the vasculature and their capacity to regenerate.

Application details

References

  1. Adler M, Mayo A, Zhou X, Franklin RA, Meizlish ML, Medzhitov R, Kallenberger SM, Alon U. Principles of Cell Circuits for Tissue Repair and Fibrosis. iScience 2020; 23(2):100841.
  2. Auth J, Müller F, Völkl S, Bayerl N, Distler JHW, Tur C, […], Mackensen A, Schett G, Bergmann C. CD19-targeting CAR T-cell therapy in patients with diffuse systemic sclerosis: a case series. Lancet Rheumatol. 2025; 7(2):e83-e93.
  3. Mothes RA, Pascual-Reguant R, Koehler J, Liebeskind J, Liebheit A, Bauherr S, […], Niesner RA, Radbruch H, Hauser AE. Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19. Nat Commun. 2023; 14(1):791.
  4. Pascual-Reguant A, Kroh S, Hauser AE. Tissue niches and immunopathology through the lens of spatial tissue profiling techniques. Eur J Immunol. 2024; 54(2):e2350484.
  5. Setten E, Castagna A, Nava-Sedeño JM, Weber J, Carriero R, Reppas A, […], Hatzikirou H, Feuerhake F, Locati M. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context. Nat Commun. 2022; 13(1):6499.
  6. Siegert E, Biesen R, Dzamukova M, Furth C, Probst M, Doellinger F, […], Krönke J, Krönke G, Alexander T. Teclistamab in relapsed systemic sclerosis after autologous haematopoietic stem cell transplantation. Ann Rheum Dis. 2025; 84(4):653-656.