Biology subjects

Dorn, I.

Publications and source records attributed to Dorn, I..

3 recordsLinked to original sources

bioRxiv2026

Self-organized hemanoids derived from human iPSCs create a niche that produces definitive extraembryonic hematopoiesis.

Manufacturing red blood cells (RBCs) from human induced pluripotent stem cells (iPSCs) can improve our understanding of embryonic erythropoiesis, foster innovative treatments for RBC-related diseases, and ultimately address clinical blood supply shortages. However, existing systems face low efficiency, enucleation failure, and uncertainty about the develop-mental wave of cultured RBCs. We successfully used self-organized hemanoids to improve iPSC-derived RBC generation. Based on the hypothesis that cellular interactions and 3D organization promote hematopoietic cell fate, we aimed to thoroughly characterize hemanoids. We visualized the spatiotemporal emergence of hematopoiesis by generating a CD43-GFP reporter iPSC line. Imaging and spatial transcriptomics analysis provided de-tailed insight into the hemanoid architecture, identifying stromal cells and hepatoblasts as potential erythropoiesis-supportive elements. The developmental stage mirrors extraembryonic hematopoiesis. Given the difficulties of accessing these early stages in vivo, our system offers a platform not only for further clinical translation but also for exploring hu-man embryonic blood wave dynamics.

developmental biology↗

bioRxiv2025

A maternal-fetal PIEZO1 incompatibility as a barrier to Neanderthal-modern human admixture

When Neanderthals and anatomically modern humans interbred, they may have faced conditional reproductive barriers. We identify a likely maternal-fetal incompatibility involving a Neanderthal PIEZO1 gene variant predicted to increase red blood cell oxygen affinity. While potentially advantageous in Neanderthals, this trait became detrimental in hybrids: heterozygous mothers carrying one Neanderthal allele could deliver insufficient oxygen to fetuses inheriting two modern alleles, reducing their survival. We tested this hypothesis using in vitro physiology, population genetic simulations, and genomic surveys. Pharmacological activation of Piezo1 in human red blood cells reproduced the high-affinity phenotype, providing a biochemical basis for impaired placental oxygen transfer. Simulations showed that maternal-fetal mismatch drives frequency-dependent selection against the Neanderthal allele, promoting demographic decline. Genomic data confirm that the variant is virtually absent in modern humans, consistent with strong purifying selection. Our findings reveal how subtle physiological mismatches plausibly restricted gene flow, contributing to Neanderthal extinction, and highlight a mechanism potentially underlying unexplained pregnancy complications today. TeaserMaternal-fetal oxygen affinity mismatches resulting from a Neanderthal PIEZO1 gene variant may have hastened their extinction. O_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC="FIGDIR/small/679417v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1132476org.highwire.dtl.DTLVardef@1bec6b5org.highwire.dtl.DTLVardef@1e7ae96org.highwire.dtl.DTLVardef@1772d17_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Conceptual model of maternal-fetal oxygen affinity mismatch caused by PIEZO1 gain-of-function (GOF) variants. Upper panel: In uncomplicated pregnancies, maternal RBCs exhibit lower hemoglobin-oxygen affinity (higher P50) than fetal RBCs, creating a gradient that facilitates placental oxygen transfer. PIEZO1 GOF variants increase maternal oxygen affinity (lower P50), narrowing this gradient and reducing fetal oxygen supply. Lower panel: Genetic inheritance scenarios illustrate how this physiological effect translates into a hybrid incompatibility. While heterozygous mothers (WT/GOF) can be healthy, pregnancies with wild-type fetuses (WT/WT) are at risk of impaired oxygen transfer, leading to growth restriction, hydrops, or fetal loss. Other maternal-fetal genotype combinations are not affected. Together, these data support a model in which PIEZO1-driven maternal-fetal mismatch acts as a non-immune reproductive barrier with relevance for both evolutionary admixture and modern pregnancy complications. C_FIG

evolutionary biology↗

bioRxiv2023

Terminal maturation of human reticulocytes to red blood cells by extensive remodelling and progressive liquid ordering of membrane lipids

In the age of "omics", lipidomics of erythropoiesis is still missing. How reticulocytes mature in the circulation into functional erythrocytes is also for the most part unknown, beyond the lipidomics level. We have characterized here the lipid content of two subpopulations of peripheral reticulocytes of different maturity and three of erythrocytes of different age. Reticulocytes undergo profound changes in membrane lipid composition as they mature in the vasculature. Sphingomyelin and cholesterol increase, whereas phosphatidylcholine and phosphatidylserine decrease, relative to total lipids, from young reticulocytes to mature erythrocytes, suggesting that the area of the membrane in liquid-ordered state increases. The relative amounts of the more than 70 phospholipid subclasses evaluated here also change in the process. As peripheral reticulocytes and erythrocytes are unable of de-novo phospholipid synthesis, such remodeling likely requires selective removal of phospholipids from the membrane or their exchange with plasma or both. It has to be investigated whether this process might involve lipid transfer proteins that, when defective, such as in neuroacantocytosis syndromes, result in altered erythrocyte morphology. These findings not only shed light on fundamental aspects of red blood cell physiology and erythropoiesis but also raise intriguing questions surrounding protein-lipid interactions, membrane architecture, and lipid trafficking mechanisms.

biochemistry↗