Biology subjects

Schallmoser, K.

Publications and source records attributed to Schallmoser, K..

6 recordsLinked to original sources

bioRxiv2026

Cell therapy for regeneration of injured donor lungs for transplantation

Donor organ shortage remains the major barrier to transplantation resulting in deaths on the waiting list. For lungs, aspiration-related injury is a common cause of donor organ discard and increases the risk of primary graft dysfunction. Currently, no effective therapies exist to repair damaged donor lungs prior to transplantation. Here, we investigated whether mesenchymal stromal cells (MSCs) from bone marrow or full-term amniotic fluid could restore severely injured donor lungs in a porcine model integrating ex vivo lung perfusion, transplantation and post-transplant follow-up (n=48; 24 donors, 24 recipients). MSCs were administered either once during ex vivo lung perfusion or repeatedly across lung perfusion and the early post-transplant period and compared with placebo treated controls. A single dose conferred only partial benefit, whereas repeated dosing restored graft function, normalized gas exchange and haemodynamics, and prevented graft dysfunction. MSCs from both sources were similarly effective in repeated regimens. These findings identify dosing schedule, rather than cell source, as key determinant of durable organ rescue and support perfusion-guided cell therapy as potentially generalizable regenerative strategy across solid-organ transplantation.

cell biology↗

bioRxiv2026

A humanized ossicle model of myelofibrosis reveals THPO-driven fibrosis, osteosclerosis and SPP1-dependent microenvironmental remodeling

Myelofibrosis (MF) is the most severe myeloproliferative neoplasm. Current therapies - except for allogeneic stem cell transplantation - are largely supportive which highlights the need for improved disease models and novel therapeutic targets. Here, we established a humanized MF model by transplanting thrombopoietin (THPO)-overexpressing human bone marrow CD34{square} cells into humanized bone marrow ossicles generated in immunodeficient NSG mice. THPO overexpression induced progressive reticulin fibrosis in vivo, accompanied by myeloid skewing, increased megakaryocyte clustering, and redistribution of human hematopoietic cells to murine spleen and femur, consistent with extramedullary hematopoiesis. THPO-driven ossicles also exhibited features of osteosclerosis, including increased trabecular bone and osteoid formation, indicating active pathological remodeling of the niche. Mechanistically, fibrosis was associated with increased SPP1/OPN expression, which was also observed in bone marrow biopsies from MF patients. Importantly, in vivo neutralization of SPP1 attenuated myeloid skewing, reduced megakaryocyte expansion, and decreased fibrosis severity, highlighting SPP1-driven niche remodeling as a potential therapeutic target in MF. This humanized MF model thus provides a translationally relevant platform to dissect microenvironment-driven MF pathogenesis and evaluate targeted therapies.

cancer biology↗

bioRxiv2024

Humanized in vivo bone marrow models orchestrate multi-lineage human hematopoietic cell development

Hematopoiesis develops in the bone marrow (BM) where multiple interactions regulate differentiation and preservation of hematopoietic stem/progenitor cells (HSPCs). Although murine BM has been extensively analyzed, the human BM microenvironment remains less understood. Immune-deficient murine models have enabled the analysis of molecular and cellular regulation of human HSPCs, which remains limited as human hematopoietic cells develop in xenogenic microenvironments. In this study, we thoroughly characterized a humanized (h) in vivo BM model, based on mesenchymal stromal cell (MSC) differentiation (called hOssicles (hOss)), and hematopoietic cell compartments generated 3 months post-transplant of CD34+ cells using single-cell RNA sequencing and cellular barcoding. Serial isolation of MSCs and HSPCs from hOss and transplant experiments revealed the dynamic nature of these hBM niches. hOss altered human hematopoietic development by modulating myeloid/lymphoid cell production and HSPC levels. Clonal tracking highlighted hematopoietic cell cross-talks between the murine BM and hOss, indicating the multipotent or more restricted lineage origin of human hematopoiesis shared in the BM sites.

cell biology↗

bioRxiv2020

Self-assembly of progenitor cells under the aegis of platelet factors facilitates human skin organoid formation and vascularized wound healing

Stem/progenitor cells can self-organize into organoids modelling tissue function and regeneration. Here we demonstrate that human platelet-derived factors can orchestrate 3D self-assembly of clonally expanded adult skin fibroblasts, keratinocytes and endothelial progenitors forming skin organoids within three days. Organoids showed distinct signaling patterns in response to inflammatory stimuli that clearly differed from separated cell types. Human induced pluripotent stem cell (hiPSC)-derived skin cell progenitors also self-assembled into stratified human skin within two weeks, healing deep wounds of immune-deficient mice. Co-transplantation of endothelial progenitors significantly accelerated vascularization. Mechanistically, platelet-derived extracellular vesicles mediated the platelet-derived trophic effects. Long-term fitness of epidermal cells was accelerated further by keratinocyte growth factor mRNA transfection. No tumorigenesis was observed upon xenografting. This permits novel rapid 3D skin-related pharmaceutical testing opportunities and facilitates development of iPSC-based skin regeneration strategies.

cell biology↗

bioRxiv2020

Extra-hematopoietic immunomodulatory role of the SCID-susceptibility gene DOCK-2 identified by stepwise maturation of human iPSCs into clonogenic mesodermal stromal progenitors

Stromal cells contribute to organ integrity as fibroblasts and to vascular stability as pericytes, in addition to their enigmatic niche function in many tissues. Their inherent immunomodulatory capacity attracted particular attention, initiating numerous clinical trials, particularly testing trophic regeneration and immunomodulation. Key stromal immune functions are still enigmatic. Here we show that dedicator of cytokinesis (DOCK-2) previously described for causing immune cell dysfunction plays a role in extra-hematopoietic immunity by regulating stromal/fibroblast immunomodulatory function. We used three independent strategies including iPSC-derived mesodermal stromal cell (MSC) lineage maturation, severe combined immunodeficiency (SCID) patient-derived cells and CRISPR/Cas9 knockout to support our findings. Human induced pluripotent stem cells (iPSCs) were generated from healthy bone marrow and umbilical cord blood-derived fibroblasts by Sendai virus-mediated transient expression of Yamanaka factors. After mesoderm induction, stromal differentiation was induced by platelet-derived growth factors under animal serum-free conditions. Under feeder-free defined conditions, iPSCs differentiated into expandable and cryo-preservable CD73+/CD105+/Tra-1-81- early iPS-MSCs lacking immunosuppressive potential. Successive maturation was required for reaching the canonical MSC phenotype and immunomodulatory competence over time, while maintaining clonogenicity, comparable to parental MSCs. Sequential RNAseq revealed acquisition of a spectrum of immune-related genes significantly expressed in mature iPS-MSCs and resembling parental MSCs immune gene expression. The DOCK-2 gene attracted our attention because mutations can cause SCID. Interestingly, SCID patient-derived fibroblast lines harboring bi-allelic DOCK-2 mutations showed significantly reduced immunomodulatory capacity compared to non-mutated control fibroblasts. CRISPR/Cas9-mediated DOCK-2 knockout in healthy iPSCs resulted in iPS-MSCs that also displayed reduced immunomodulatory capacity, thus confirming a role of DOCK-2 in stromal immune function. At a mechanistic level, DOCK-2 deficiency resulted in disturbed subcellular localization of CDC42. This provides first evidence for an extra-hematopoietic immunomodulatory role of DOCK-2 in stromal cells, previously considered restricted to hampering immune cell migration/function resulting in SCID. We may speculate that some of the signs and symptoms of persisting immune disease after successful hematopoietic stem cell transplantation in SCID patients could at least in part be due to mutations, like DOCK-2-/-, permissive outside the hematopoietic immune system, as evidenced also by the increased virus infection susceptibility of DOCK-2 deficient fibroblasts.

immunology↗

bioRxiv2019

Extracellular vesicles from therapeutic grade allogeneic human placental stromal cells induce angiogenesis and modulate immunity

Nanoparticles can acquire a protein corona defining their biological identity. Corona functions were not yet considered for cell-derived extracellular vesicles (EVs). Here we demonstrate that nanosized EVs from therapy-grade human placental-expanded (PLX) stromal cells are surrounded by an imageable and functional protein corona when enriched with permissive technology. Scalable EV separation from cell-secreted soluble factors via tangential flow-filtration and subtractive tandem mass-tag proteomics revealed significant enrichment of predominantly immunomodulatory and proangiogenic proteins. Western blot, calcein-based flow cytometry, super-resolution and electron microscopy verified EV identity. PLX-EVs protected corona proteins from protease digestion. EVs significantly ameliorated human skin regeneration and angiogenesis in vivo, induced differential signaling in immune cells, and dose-dependently inhibited T cell proliferation in vitro. Corona removal by size-exclusion or ultracentrifugation abrogated angiogenesis. Re-establishing an artificial corona by cloaking EVs with defined proangiogenic proteins served as a proof-of-concept. Understanding EV corona formation will improve rational EV-inspired nanotherapy design.

cell biology↗