Biology subjects

Kissner, M.

Publications and source records attributed to Kissner, M..

5 recordsLinked to original sources

bioRxiv2026

Proteomic and Kinetic Analyses Reveal Discordant Apolipoprotein Turnover and Support a Revised Model of Human Lipoprotein(a) Metabolism

Objective: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease composed of apolipoprotein(a) [APO(a)] covalently linked to apolipoprotein B100 (APOB). Although plasma Lp(a) concentrations are largely genetically determined, the mechanisms governing Lp(a) metabolism after particle assembly remain poorly understood. We sought to define the Lp(a) proteome and determine the metabolic behavior of APO(a) and APOB within circulating Lp(a) particles using integrated proteomic, kinetic, and imaging approaches. Approach and Results: Sixteen healthy adults underwent stable isotope tracer studies with 2H3-L-leucine and 2H5-glycerol. Lp(a) particles were isolated by APO(a)-specific immunoprecipitation for high-resolution liquid chromatography-mass spectrometry and kinetic analyses, and extracellular vesicles (EVs) were characterized by imaging flow cytometry and super-resolution microscopy. Proteomic analysis identified 92 proteins associated with immuno-isolated Lp(a), enriched in pathways related to immunity, coagulation, and atherogenesis. Lp(a)-APO(a) exhibited a mean fractional clearance rate of 0.04 pools/day, whereas Lp(a)-APOB cleared approximately sevenfold faster (0.25 pools/day), independent of plasma Lp(a) concentration or APO(a) isoform size. Both APO(a) and APOB were detected on circulating EVs, suggesting that EVs may contribute to post-secretory Lp(a) particle remodeling. Conclusion: These integrated human studies demonstrate marked discordance between APO(a) and APOB turnover within circulating Lp(a) particles, challenging the prevailing assumption that both apolipoproteins behave as a single metabolic unit after Lp(a) assembly and supporting a revised model of human Lp(a) metabolism.

physiology↗

bioRxiv2026

Cytokinesis Arrest-induced Binucleation of Macrophages ProducesHighly Efficient Efferocytes

Efferocytosis, the phagocytic clearance of dying cells and debris, supports tissue homeostasis, immune tolerance, and inflammation resolution, whereas its failure contributes to autoimmunity, atherosclerosis, aging, and impaired tissue repair. Although many molecular regulators of efferocytosis have been defined, less is known about whether macrophages can be reprogrammed into a distinct cellular state with intrinsically enhanced efferocytosis capacity. Guided by a CRISPR screen, we found that Pdcd6ip loss induces cytokinesis arrest and binucleation, creating macrophages with superior efferocytic function. Binucleated Pdcd6ip-/- bone marrow-derived macrophages demonstrate a coordinately enhanced multi-corpse capture and processing, and resolution response, and acquired a distinct transcriptomic signature. In vivo, Pdcd6ip deletion enhanced splenic macrophage efferocytosis, reduced autoimmune responses after repeated apoptotic cell challenge, and promoted plaque stability without metabolic or hematologic changes. PDCD6IP perturbation similarly increased binucleation and engulfment in human macrophage-like cells. Thus, incomplete cytokinesis represents an unrecognized route to macrophage specialization with enhanced efferocytosis capacity.

cell biology↗

bioRxiv2026

Supramolecular hydrogel viscoelasticity regulates in situ tertiary lymphoid neogenesis

Tertiary lymphoid structures (TLSs) are organized three-dimensional immune niches associated with improved antitumor immunity, which has galvanized efforts to induce them artificially using biomaterials. However, these strategies have largely focused on soluble cue delivery, leaving the role of scaffold physical properties poorly understood. Here, we developed injectable, liposome-crosslinked supramolecular hydrogels spanning soft and stiff formulations to determine how scaffold mechanical properties regulate in situ tertiary lymphoid neogenesis. The formulations differed in their viscoelastic properties while maintaining broadly comparable release of ovalbumin and LIGHT. Soft hydrogels underwent distributed cellular infiltration and material replacement, transitioning from an early myeloid-rich response to vascularized, lymphoid-dominant tissues containing B-cell-rich aggregates adjacent to T-cell regions, with B-cell organization peaking at day 14. Single-cell RNA sequencing revealed that transient interferon-associated neutrophil and macrophage states in the early niche preceded the emergence of TLS-associated transcriptional programs across lymphoid and myeloid populations. In contrast, stiff hydrogels resisted infiltration and perpetuated a niche dominated by activated myeloid cells with limited lymphoid organization. Prophylactically implanted soft hydrogels improved early melanoma control relative to stiff hydrogels under checkpoint blockade, and a single soft-hydrogel implantation restrained tumor growth even without checkpoint blockade. Together, these findings establish scaffold mechanics and remodeling as active regulators of engineered immune-tissue organization and provide design principles for directing the development of local TLS-like niches.

bioengineering↗

bioRxiv2026

FGF Signaling Potentiates Müller Glia for Mammalian Retinal Regeneration

Muller glia possess latent regenerative potential that could be harnessed to restore retinal neurons lost to injury or disease. Although fibroblast growth factor (FGF) signaling is upregulated following retinal damage, its role in mammalian retinal regeneration remains unclear. Here, we investigated the function of FGF signaling in Muller glial reprogramming using genetic, pharmacological, and single-cell transcriptomic approaches. Activation of FGF signaling alone was insufficient to induce Muller glial proliferation in the mouse retina. However, conditional deletion of FGFR1/2 in Muller glia abolished regenerative responses induced by multiple independent pathways, demonstrating that FGF signaling is essential for regenerative competence. Mechanistically, loss of FGF signaling impaired sustained ERK/MAPK activation following injury, while MEK/ERK inhibition phenocopied the regenerative defect. Conversely, constitutive MEK activation induced limited Muller glial proliferation in the absence of injury. Although STAT3/5 inhibition synergized with Activin-A to promote robust proliferation and neurogenic gene expression, it failed to rescue regeneration in FGF-deficient Muller glia. Single-cell RNA sequencing revealed that FGF signaling suppresses multiple anti-regenerative programs, including Hes1, S1pr1, p27, NF-{kappa}B, and p300/CBP activity. Together, these findings identify FGF signaling as a critical permissive regulator of mammalian retinal regeneration that potentiates Muller glia through sustained ERK activation and suppression of transcriptional barriers to regeneration.

Developmental Biology↗

bioRxiv2024

Single-cell multimodal profiling of monocytes reveals diverse phenotypes and alterations linked to cardiovascular disease risks

Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. The Cell surface expression of CD14 and CD16 has historically identified them, however, recent single-cell studies have uncovered that they are much more heterogeneous than previously realized. We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to describe the comprehensive transcriptional and phenotypic landscape of 437,126 monocytes. This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi, monocyte-platelet aggregates, and non-classical, as well as several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- non-classical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique functions, developmental trajectories, transcriptional regulation, and tissue distribution. Moreover, we revealed alterations associated with cardiovascular disease (CVD) risk factors, including race, smoking, and hyperlipidemia, and the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. This integrative and cross-species comparative analysis provides a unique resource to compare alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in CVD and the potential for targeted therapies. SummaryMultimodal profiling provides a comprehensive phenotypic and transcriptional understanding of monocytes in health and cardiovascular disease risk states.

genomics↗