Biology subjects

Shivdasani, R. A.

Publications and source records attributed to Shivdasani, R. A..

7 recordsLinked to original sources

bioRxiv2026

A unique intestinal epithelial cell that expresses canonical lymphoid genes

Enterocytes and intestinal secretory cells harbor innate immunity. However, certain transcriptional programs -even beyond rearranged T- and B-cell receptor genes- are considered the exclusive purview of adaptive immune cells, including abundant and diverse intestinal intra-epithelial lymphocytes (IELs). Here, we identify and characterize columnar intestinal secretory cells that co-express classic epithelial and lymphoid genes, including Ptprc, Cd3e, Cd8a, and Gzma/b but not T- or B-cell receptors. These previously unrecognized epithelium-derived lymphoid-like cells (EDLCs) differ from any known resident cell type, including IELs or tuft cells. Rare in healthy mouse and human intestines, their numbers increase upon IL-25 stimulation or IL-10 receptor deficiency in vivo and upon IL-13 stimulation in vitro. EDLC chromatin is uniquely accessible at thousands of cis-elements, including lymphoid and epithelial loci. These findings reveal a transcriptionally and epigenetically distinct intestinal epithelial derivative that expresses prominent lymphoid character.

cell biology↗

bioRxiv2025

Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation

HIGHLIGHTSO_LIDelineation of chromatin and mRNA dynamics of intestinal secretory differentiation C_LIO_LIPaneth cells have few unique enhancers and share mRNAs and TFs with goblet cells C_LIO_LIUnlike other secretory derivatives, goblet and Paneth cells are not specified per se C_LIO_LINiche factors, especially BMP signaling, define goblet and Paneth phenotypes C_LI Enterocytes and four secretory cell types derive from stem cells located in intestinal crypts. Whereas secretory goblet and Paneth cells have long been considered distinct, we find high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of sibling enteroendocrine or tuft cells. Mouse and human goblet and Paneth cells express extraordinary fractions of selective antimicrobial genes, reflecting specific and variable gene responses to local niche signals. Wnt signaling retains few ATOH1+ secretory daughters in crypt bottoms, where an absence of BMP signaling potently induces Paneth features; those that move away from crypt bottoms acquire classic goblet properties. These post-mitotic cellular phenotypes and their underlying accessible cis-elements interconvert readily. Thus, goblet and Paneth properties represent alternative manifestations of a single versatile signal-responsive secretory cell. These findings reveal exquisite niche-dependent cell plasticity and the cis-regulatory dynamics of an updated unitarian model of the intestinal epithelial lineage.

cell biology↗

bioRxiv2025

Dynamic Reprogramming of Stromal Pdgfra-expressing cells during WNT-Mediated Transformation of the Intestinal Epithelium

Stromal fibroblasts regulate critical signaling gradients along the intestinal crypt-villus axis1 and provide a niche that supports adjacent epithelial stem cells. Here we report that Pdgfra-expressing fibroblasts secrete ligands that promote a regenerative-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Using a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations, we revealed a dynamic reprogramming of Pdgfra+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFB signaling is notably induced in Pdgfra+ fibroblasts in the presence of oncogenic epithelium, and TGFB was essential to sustain regenerative-like growth of organoids ex vivo. Genetic reduction of Cdx2 in the {beta}-catenin mutant epithelium elevated the fetal-like/regenerative transcriptome and accelerated WNT-dependent onset of oncogenic transformation of the tissue in vivo. These results demonstrate that Pdgfra+ fibroblasts are activated during WNT-driven oncogenesis to promote a regenerative state in the epithelium that precedes and facilitates formation of tumors.

cancer biology↗

bioRxiv2023

Structure, signals, and cellular elements of the mouse gastric mesenchymal niche

PDGFRA-expressing mesenchyme provides a niche for intestinal stem cells. Corresponding compartments are unknown in the stomach, where corpus and antral glandular epithelia have similar niche dependencies but are structurally distinct from the intestine and from each other. Previous studies considered antrum and corpus as a whole and did not assess niche functions. Using high-resolution imaging and sequencing, we identify regional subpopulations and niche properties of purified mouse corpus and antral PDGFRA+ cells. PDGFRAHi sub-epithelial myofibroblasts are principal sources of BMP ligands in both gastric segments; two molecularly distinct groups distribute asymmetrically along antral glands but together fail to support epithelial organoids in vitro. In contrast, strategically positioned PDGFRALo cells that express CD55 enable corpus and antral organoid growth in the absence of other cellular or soluble factors. Our study provides detailed insights into spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for stem cell support.

cell biology↗

bioRxiv2020

Creb5 establishes the competence for Prg4 expression in articular cartilage

A hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by the Prg4 gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-{beta} and EGFR signaling to induce Prg4 expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-{beta} and EGFR signals to induce Prg4 expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction of Prg4 by TGF-{beta}. Our results indicate that Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage.

molecular biology↗

bioRxiv2020

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients. SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.

cancer biology↗

bioRxiv2018

The Lineage-Specific Transcription Factor CDX2 Navigates Dynamic Chromatin to Control Distinct Stages of Intestine Development

Lineage-restricted transcription factors, such as the intestine-specifying factor CDX2, often have dual requirements across developmental time. Embryonic-loss of CDX2 triggers homeotic transformation of intestinal fate, while adult-onset Cdx2-loss compromises critical physiological functions but preserves intestinal identity. It is unclear how such diverse requirements are executed across the developmental continuum. Using primary and engineered human tissues, mouse genetics, and a multi-omics approach, we demonstrate that divergent CDX2 loss-of-function phenotypes in embryonic versus adult intestines correspond to divergent CDX2 chromatin-binding profiles in embryonic versus adult stages. CDX2 binds and activates distinct target genes in developing versus adult mouse and human intestinal cells. We find that temporal shifts in chromatin accessibility correspond to these context-specific CDX2 activities. Thus, CDX2 is not sufficient to activate a mature intestinal program, but rather, CDX2 responds to its environment, targeting stage-specific genes to contribute to either intestinal patterning or maturity. This study provides insights into the mechanisms through which lineage-specific regulatory factors achieve divergent functions over developmental time.

developmental biology↗