Biology subjects

Scheding, S.

Publications and source records attributed to Scheding, S..

4 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↗

bioRxiv2025

Combined multi-color immunofluorescence staining and spatial in situ mRNA expression analysis identifies potential fibrosis drivers in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer. Bone marrow (BM) fibrosis in ALL has been associated with adverse outcomes, however, little is known about the mechanisms that cause fibrosis in ALL. Therefore, we established a novel and advanced analysis method by combining multi-color immunofluorescence staining with in-situ RNA expression analysis (RNAscope(R)) investigate the spatial expression of putative fibrotic drivers in ALL bone marrows. We analyzed standard BM biopsies from pediatric ALL patients. Sequential 5-color immunofluorescence (IF) staining with CD45, CD271, CD31, CD34 and DAPI was used to identify different BM cell types. Combined RNAscope(R) and IF staining was established for spatial mRNA expression analysis of transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor alpha 1 (PDGFA1), which are known to play major roles in primary myelofibrosis (PMF). PMF and normal BM samples served as controls. As expected, ALL bone marrows showed high cellularities and prominent populations of blast cells. CD271+ MSC density was increased in ALL and was associated with fibrosis in a similar manner as observed for PMF. TGFB1 and PDGFA1 expression was considerably increased in ALL megakaryocytes (MKs) compared to PMF patients and normal controls. Furthermore, MK TGFB1 and PDGFA1 expression intensities in fibrotic ALL correlated with fibrosis grade. TGFB1 and PDGFA1 were also expressed in leukemic blasts, however at lower intensities compared to ALL MKs. Taken together, advanced in-situ RNA and IF staining not only revealed increased expression of TGFB1 and PDGFA1 in fibrotic pediatric ALL, but also identified ALL blasts and MKs as their cellular origin at the single cell level. These novel data strongly suggest a role of these cytokines as potential fibrosis drivers in ALL. More broadly, our findings demonstrate that combined RNA and surface marker analysis is a powerful tool to provide new and valuable insights into bone marrow pathophysiology.

cell biology↗

bioRxiv2022

Single-cell RNA sequencing identifies phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow

Hematopoiesis is regulated by the bone marrow (BM) stroma. However, cellular identities and functions of the different BM stromal elements in humans remain poorly defined. Based on single-cell RNA sequencing, we systematically characterized the BM stromal compartment which led to the identification of six transcriptionally and functionally distinct stromal cell populations. Stromal cell differentiation hierarchy was recapitulated based on RNA velocity analysis, in vitro proliferation capacities and differentiation potentials. Potential key factors that govern the transition from stem and progenitor cells to fate- committed cells were identified. In silico cell-cell communication prediction and in situ localization analyses demonstrated distinct hematopoietic stromal cell niches in specific BM locations, which used either the CXCL12 or SPP1 axis as the major hematopoiesis-regulating mechanism. These findings provide the basis for a comprehensive understanding of the cellular complexity of the human BM microenvironment and the intricate stroma- hematopoiesis crosstalk mechanisms, thus refining our current view on hematopoietic niche organization.

cell biology↗