Biology subjects

Elisseeff, J.

Publications and source records attributed to Elisseeff, J..

7 recordsLinked to original sources

bioRxiv2026

Targeting cellular senescence alleviates bone marrow aging

Aging of the hematopoietic system impairs hematopoietic stem cell (HSC) function and alters bone marrow niche behavior, increasing susceptibility to anemia, infections, and hematologic malignancies. Here, pharmacologic clearance of senescent cells with the PROTAC compound 753b simultaneously targeting BCL-xL and BCL-2 reverses key secretory, transcriptional, and functional hallmarks of hematopoietic aging with low toxicity, restoring balanced lineage output. Single-cell RNA sequencing further demonstrates that 753b treatment attenuates aging-associated transcriptional signatures in HSCs, while selectively eliminating senescent, pro-survival niche cells without grossly perturbing niche composition. Functionally, 753b suppresses pro-inflammatory cues from both niche and hematopoietic cells including those emanating from neutrophil progenitors, rebalancing global bone marrow secretory ecosystem across stromal and hematopoietic compartments. Collectively, we identify 753b-induced senescent cell clearance as a powerful strategy to rejuvenate aged hematopoiesis and re-establish homeostatic communication between HSCs and their microenvironment, with implications for mitigating age-related hematologic dysfunction and improving hematologic health in older individuals.

cell biology↗

bioRxiv2026

3D, multi-omic imaging reveals molecular biomarkers of the pre-metastatic niche in lung cancer

The recurrence rate following complete surgical resection of primary non-small cell lung cancer is as high as 55%, yet no approach currently exists to evaluate the risk of local recurrence. The premetastatic paradigm is the recognition that metastasis is preceded by reprogramming naive tissues to prime a microenvironment for tumor cell survival and subsequent reactivation. Identification of biomarkers of the pre-metastatic niche would allow us to evaluate a patients risk of local relapse in the normal lung parenchyma surrounding the resected tumor. We designed a workflow incorporating in vivo modelling, radiology, and deep learning-guided three-dimensional (3D) imaging, spatial proteomics, and transcriptomics to identify previously unreported signals associated with the early transformation of the lung parenchyma announcing regional metastasis. We curated biorepository spanning timepoints before and after resection of primary Lewis Lung Carcinoma (LLC) tumors. Using radiology and cellular resolution 3D histology, we calculated the number and distribution of metastases in mouse lungs and developed an algorithm to guide placement of spatial proteomics and transcriptomics to regions containing early micro-metastases and the pre-metastatic microenvironment. Molecular and tissue features associated with presence, size, and location of metastases guided the identification of both myeloid (F4/80) and senescent (p16/p21) cell signatures in the premetastatic and metastatic environments. Finally, multiparametric flow cytometry of metastatic lungs in a senescence reporter GEMM (tdTomato-p16 INKA mice) resolved senescent cells including alveolar macrophages as the cellular phenotypes associated with these early premetastatic signatures. Altogether, this work highlights a novel AI-assisted approach for detection of biomarkers of tissue remodeling during lung cancer invasion.

bioengineering↗

bioRxiv2025

Matrix stiffness induces endothelial network senescence

Identifying the drivers of cellular senescence that contribute to the decline in tissue function related to aging- and disease is critical for developing restorative interventions. Here, we investigated how increased mechanical stress from extracellular matrix (ECM) stiffening shapes endothelial cell (EC) senescence. We developed a 3D human in vitro model that decouples mechanical stress from inflammatory or biochemical inputs, enabling the study of senescence responses to tissue stiffening alone. We found that matrix stiffening induces an EC senescence phenotype with elevated p16/p21 and an immunomodulatory senescence-associated secretory phenotype (SASP), in the absence of inflammatory signals. This mechano-induced senescence state engaged a Notch-JNK-FOS signaling axis, and pharmacologic inhibition of Notch attenuated stiffness-induced senescence. Supporting the translational relevance of this mechanism, analysis of fibrotic capsule tissue from patients with synthetic breast implants, a model of localized, mechanically driven fibrosis, revealed increased p16+Notch1+ endothelial populations. Complementary single-cell RNA sequencing data confirmed their enrichment in Notch/JNK- and SASP-related gene programs. Together, these findings define vascular senescence as a mechanosensitive process and identify tissue stiffening as an upstream aging signal. Our work offers a human-relevant platform for studying targetable stages of endothelial mechanoaging.

bioengineering↗

bioRxiv2025

Antibiotic-induced microbiota depletion impairs the pro-regenerative response to a biological scaffold in mice

Therapeutic biological scaffolds promote tissue repair primarily through the induction of type 2 immunity. However, systemic immunological factors-including aging, sex, and previous infections-can modulate this response. The gut microbiota is a well-established modulator of immune function across organ systems, yet its influence on type 2-mediated repair remains underexplored. Here, we establish a bidirectional relationship between the gut microbiota and biological scaffold-mediated tissue repair. Utilizing a conventionalized germ-free mouse, we demonstrate that scaffold implantation induces compositional and functional changes in the gut microbiome, particularly affecting amino acid biosynthesis. Additionally, in a model of antibiotic-induced microbiota depletion (AIMD), we show that dysbiosis disrupts key immune regulators of type 2 immunity, including reductions in eosinophils, pro-regenerative macrophages, and IL-4-producing CD4+ T cells. At 6 weeks post-scaffold implantation, we observed a significant decrease in myocytes with centrally located nuclei alongside an upregulation in pro-fibrotic gene expression with antibiotic treatment. These findings provide insights into the influence of the gut microbiota on type 2-mediated tissue repair. Significance StatementAntibiotics are routinely administered perioperatively to prevent infection during surgeries and biomaterial implantation. Here, we demonstrate that antibiotic-induced microbiota depletion disrupts the type 2 immune response critical for biomaterial-mediated tissue repair. Our findings highlight the gut microbiota as a determinant of constructive healing and a potential contributor to inter-individual variability in responses to biologic scaffolds.

immunology↗

bioRxiv2025

Murine gut microbiota dysbiosis via enteric infection modulates the foreign body response to a distal biomaterial implant

The gut microbiota influences systemic immunity and the function of distal tissues, including the brain, liver, skin, lung, and muscle. However, the role of the gut microbiota in the foreign body response (FBR) and fibrosis around medical implants is largely unexplored. To investigate this connection, we perturbed the homeostasis of the murine gut microbiota via enterotoxigenic Bacteroides fragilis (ETBF) infection and implanted the synthetic polymer polycaprolactone (PCL) into a distal muscle injury. ETBF infection in mice led to increased neutrophil and {gamma}{delta} T cell infiltration into the PCL implant site. ETBF infection alone promoted systemic inflammation and increased levels of neutrophils in the blood, spleen, and bone marrow. At the PCL implant site, we found significant changes in the transcriptome of sorted fibroblasts but did not observe gross ETBF- induced differences in the fibrosis levels after 6 weeks. These results demonstrate the ability of the gut microbiota to mediate long-distance effects such as immune and stromal responses to a distal biomaterial implant. Significance StatementThe foreign body response to implants leads to chronic inflammation and fibrosis that can be highly variable in the general patient population. Here, we demonstrate that gut dysbiosis via enteric infection promoted systemic inflammation and increased immune cell recruitment to an anatomically distant implant site. These results implicate the gut microbiota as a potential source of variability in the clinical biomaterial response and illustrate that the local tissue environment can be influenced by host factors that modulate systemic interactions.

bioengineering↗

bioRxiv2023

Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence

Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients and recurrence can also occur. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy. We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response. ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell markers expression suggesting strong activity of these cells. Cancer-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic response, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by cancer-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient. These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.

cancer biology↗

bioRxiv2019

Interleukin 17 and senescence regulate the foreign body response

Synthetic biomaterials and medical devices suffer to varying levels from fibrosis via the foreign body response (FBR). To explore mechanistic connections between the immune response and fibrosis from the FBR, we first analyzed fibrotic capsule surrounding human breast implants and found increased numbers of interleukin (IL)17-producing {gamma}{delta}+ T cells and CD4+ TH17 cells as well as senescent cells. Further analysis in a murine model demonstrated an early innate IL17 response to synthetic implants, mediated by innate lymphoid cells and {gamma}{delta}+ T cells, was followed by a chronic adaptive antigen dependent CD4+ TH17 cell response. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to materials and the development of p16INK4a senescent cells. Treatment with a senolytic agent reduced IL17 expression and fibrosis. Discovery of a feed-forward loop between the TH17 and senescence response to synthetic materials introduces new targets for therapeutic intervention in the foreign body response.

immunology↗