Biology subjects

Tal, R.

Publications and source records attributed to Tal, R..

3 recordsLinked to original sources

bioRxiv2025

Dynamics of Macrophage Polarization Reveal Unique Phenotypes During Mouse Postpartum Uterine Remodeling

BackgroundMacrophages play essential roles in uterine physiology during pregnancy and the postpartum (PP) period. In various organ systems, macrophages exhibit distinct M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization states, the balance of which is key not only in scarless wound healing but also in pathological fibrosis. While macrophages are central players in PP uterine remodeling, their polarization dynamics during this period and associated spatial distribution remain largely unknown. MethodsUterine tissues were collected from C57BL/6J wild-type mice at various PP days (PPD 1, 3, 7, 14, 21, 28) and non-pregnant controls. Multicolor flow cytometry was used to analyze immune populations and macrophage polarization states. Macrophage polarization was determined using CD86 (M1 marker) and CD206 (M2 marker). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to examine the colocalization of M1 and/or M2 markers alongside F4/80 to assess macrophage polarization status and tissue distribution. ResultsOn PPD1, uterine macrophage numbers were higher compared to all other time points, with significantly increased M2 macrophages (CD86-CD206+) (43% p<0.0001) compared to PPD3 (5.1%), PPD7 (2.4%), PPD14 (2.3%), and non-pregnant (1.9%). A rapid polarization shift to M1 macrophages (CD86+CD206-) occurred on PPD3 (50.6%), PPD7 (66.5%), and PPD14 (58.8%) compared to PPD1 (11.9% p<0.0001). Additionally, there was a trend of increased M2 macrophages on PPD21 (10%) and PPD28 (5%). We observed a unique macrophage subset of mixed phenotype (co-expressing CD86+CD206+) significantly higher on PPD 1 (37.2% p<0.05) compared to NP (7.8%), PPD7 (11.6%), and PPD14 (26.4%). IF co-staining confirmed these dynamics, showing the highest percentage of macrophages co-expressing CD206+F4/80+ on PPD1 (77.2%), significantly higher than all other time points. IHC revealed the specific temporal and spatial distribution of F4/80+ and CD206+ cells within the uterine endometrial stroma adjacent to the myometrial junction in the early PP period. ConclusionsThe predominance of M2-polarized macrophages on PPD1 followed by a rapid shift to M1 phenotype from PPD3 to PPD14 indicates an evolving inflammatory response during the early postpartum period. Repolarization to M2 profile on PPD21, along with increased abundance of a mixed population (M1/M2), uncovers the dynamic complexity of macrophage polarization during PP uterine remodeling, providing new insights into scarless uterine tissue repair.

immunology↗

bioRxiv2021

The transcriptional hallmarks of intra-tumor heterogeneity across a thousand tumors

Each tumor contains malignant cells that differ in genotype, phenotype, and in their interactions with the tumor micro-environment (TME). This results in distinct integrated cellular states that govern intra-tumor heterogeneity (ITH), a central challenge of cancer therapeutics. Dozens of recent studies have begun to describe ITH by single cell RNA-seq, but each study typically profiledonly a small number of tumors and provided a narrow view of transcriptional ITH. Here, we curate, annotate and integrate the data from 77 different studies to reveal the patterns of ITH across 1,163 tumor samples covering 24 tumor types. Focusing on the malignant cells, we find thousands of transcriptional ITH programs that can be described by 41 consensus meta-programs (MPs), each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many different tumors. The MPs cover diverse cellular processes and differ in their cancer-type distribution. General MPs associated with processes such as cell cycle and stress vary within most tumors, while context-specific MPs reflect the unique biology of particular cancer types, often resembling developmental cell types and suggesting the co-existence of variable differentiation states within tumors. Some of the MPs are further associated with overall tumor proliferation or immune state, highlighting their potential clinical significance. Based on functional similarities among MPs, we propose a set of 11 hallmarks that together account for the majority of observed ITH programs. Given the breadth and scope of the investigated cohort, the MPs and hallmarks described here reflect the first comprehensive pan-cancer description of transcriptional ITH.

cancer biology↗

bioRxiv2019

Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity

Cultured cell lines are the workhorse of cancer research, but it is unclear to what extent they recapitulate the cellular heterogeneity observed among malignant cells in tumors, given the absence of a native tumor microenvironment. Here, we used multiplexed single cell RNA-seq to profile ~200 cancer cell lines. We uncovered expression programs that are recurrently heterogeneous within many cancer cell lines and are largely independent of observed genetic diversity. These programs of heterogeneity are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-to-mesenchymal transition, and protein maturation and degradation. Notably, some of these recurrent programs recapitulate those seen in human tumors, suggesting a prominent role of intrinsic plasticity in generating intra-tumoral heterogeneity. Moreover, the data allowed us to prioritize specific cell lines as model systems of cellular plasticity. We used two such models to demonstrate the dynamics, regulation and drug sensitivities associated with a cancer senescence program also observed in human tumors. Our work describes the landscape of cellular heterogeneity in diverse cancer cell lines, and identifies recurrent patterns of expression heterogeneity that are shared between tumors and specific cell lines and can thus be further explored in follow up studies.

cancer biology↗