Elaine E. Storm’s research while affiliated with University of California, San Francisco and other places

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Publications (11)


Lung-innervating neurons expressing Tmc3 can induce broncho-constriction and dilation with direct consequences for the respiratory cycle
  • Preprint

August 2023

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52 Reads

Jens Kortmann

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Kevin Huang

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Shannon J. Turley

Sensory neurons of the vagal ganglia (VG) innervate lungs and play a critical role in maintaining airway homeostasis. However, the specific VG neurons that innervate lungs, and the mechanisms by which these neurons sense and respond to airway insults, are not well understood. Here, we identify a subpopulation of lung-innervating VG neurons defined by their expression of Tmc3 . Single cell transcriptomics illuminated several subpopulations of Tmc3+ sensory neurons, revealing distinct Piezo2 - and Trpv1 -expressing subclusters. Furthermore, Tmc3 deficiency in VG neurons leads to global and subcluster specific transcriptional changes related to metabolic and ion channel function. Importantly, we show that broncho-constriction and dilation can be modulated through inhibition or activation of Tmc3+ VG neurons resulting in a decrease or increase of end-expiratory lung volume, respectively. Together, our data show that Tmc3 is a marker of lung-innervating neurons and may play a pivotal role in maintaining fundamental inspiratory and expiratory processes. Significance Harnessing the neuronal mechanisms that regulate lung function offers potential alternatives to existing corticosteroid treatment regimens for respiratory illness associated with acute bronchoconstriction including asthma, COPD, and emphysema. Our findings define Transmembrane channel-like 3 , Tmc3 , as a marker of lung-innervating sensory neurons, identify distinct subpopulations of Tmc3 + neurons with unique transcriptional profiles, and show that activation or inhibition of these neurons has a significant impact on airway function. Our work highlights potential avenues of novel targeted intervention in respiratory conditions driven by dysfunctional neuronal reflexes.


Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells

August 2023

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55 Reads

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14 Citations

Cell Stem Cell

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that β-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.


Abstract A039: RAS signaling strength determines phenotypic response in the colon

May 2023

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17 Reads

Molecular Cancer Research

The RAS (KRAS, NRAS and HRAS) genes are the most frequently mutated in cancer and are highly specific to tissue type by isoform and codon, yet the underlying cause for this selection is unknown. Mutations in KRAS, but not NRAS, frequently occur and act as oncogenic events in colorectal cancer. Biochemically, activating mutations in RAS increase the abundance of the GTP-bound active state, however, the position and substitution of the mutated amino acid affect the ‘on’ and ‘off’ rates of the RAS-GTP/GDP cycle. Alterations in codon 61 result in the largest accumulation of RAS-GTP. While this leads to robust pathway activation, codon 61 mutations are rarely observed in KRAS-mutant colorectal cancers. To study the effect of the isoform and codon mutations in colorectal tumor formation, we engineered mouse models to express codon 12 or 61 mutations in Kras and Nras. Our mouse models recapitulate the clinical RAS isoform and allelic selection. We found Kras G12D provided the greatest proliferative effect. To further understand this allelic selection, we investigated the interplay between RAS signaling strength and intestinal epithelial cell composition. We observed a correlation between RAS signaling strength and induction of stem cell differentiation. Together, our data provide insights to the preference for KRAS mutations in human colorectal cancers and provides a rationale for allelic selection. Citation Format: Amanda R. Moore, Sandra Melo Carlos, Elaine E. Storm, Lisa M. McGinnis, Shiva Malek, Frederic J. de Sauvage. RAS signaling strength determines phenotypic response in the colon [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A039.


Fig. 2. Generation of Rock1, Rock2 and Rock1:Rock2 conditional knockout strains. (A) Targeting strategy for the generation of Rock1 flox/flox and Rock2 flox/flox mice. Conditional Rock1 and Rock2 alleles were generated by the insertion of loxP sites flanking exons 3 and 4 and exon 3 respectively. (B) Mice with indicated genotypes were treated with TMX and splenic tissue was harvested for quantitative RT-PCR (qPCR) measurement of Rock1 and Rock2. Data are represented as mean with S.D. n = 3-5 mice per group. (C) Western blot analysis of cell lysates from spleens blotted with antibodies to Rock1, Rock2 or β -actin. Tissue was derived from either TMX treated Rock1 +/+ ;Rock2 +/+ ;R26R Cre ERT2 or Rock1 flox/flox ; Rock2 flox:flox ;R26R Cre ERT2 mice.
Fig. 3. Global deletion of both Rock1 and Rock2 in adult mice is fatal. (A) Kaplan-Meier survival curves for indicated strains over time plotted as percent survival. (B) Weight measurement over time shown as percent weight loss. Data in are represented as mean with S.D. Shaded blue area indicates the time during which the 5 TMX injections were given. For each experiment in A and B, 7-10 mice per genotype were monitored over time.
Fig. 4. Global deletion of both Rock1 and Rock2 causes malnutrition and cytopenia. (A) Serum chemistry and (B) CBC measurements on day 12 from the initiation of TMX treatment in WT (green) and R1;R2cKO strains (red). Abbreviations: TG (triglycerides), BUN(Blood Urea Nitrogen), RBC(Red Blood Cells), HGB(Hemoglobin), WBC(White Blood Cells). Data are representative of 3-5 independent experiments. Data are represented as mean with S.D. n = 3-5 mice per group. *P < 0.05 t-test, relative to control.
Fig. 5. Genetic ablation of Rock1 and Rock2 in adult mice leads to a reduction in mature leukocyte populations. Enumeration of LSK cells (Lineage low,c-Kit + ,Sca-1 + ), BM cells and splenocytes derived from WT or (A) R1cKO and (B)R2cKO mice on day 30 following the last TMX injection. (C). Experimental design for assessing leukocytes in R1;R2cKO mice. (D) Enumeration of total BM cells or splenocytes from WT or R1;R2cKO mice at different times post-TMX treatment. (E) Quantification of the indicated leukocyte populations (B cells: CD45 + B220 + , T cells: B220 -CD3e + CD90.2 + CD45 + , Neutrophils-: B220 -CD3e CD90.2 -Siglec F Ly6G + CD45 + , Eosinophils:B220 -CD3e CD90.2 -Ly6G Siglec F + CD45 + , Macrophages:B220 -CD3e CD90.2 -Ly6G Siglec F CD11b F4/80 + CD45 + ) from BM of WT or R1;R2cKO mice harvested on day 6 from the first TMX treatment. LSK cells and individual leukocyte populations were enumerated using FACS while total BM and splenocytes were counted on a cell counter. Data are represented as mean with S.D. n = 3-5 mice per group. *P < 0.05,**P < 0.005,***P < 0.005 t-test, relative to control.
Fig. 6. Repopulation of host CD45.1 derived hematopoietic cells in Rock1 flox/flox ;Rock2 flox:flox ;R26 Cre-ERT2 -> WT BM chimeras. (A) Experimental design of chimera generation.(B) Kaplan-Meier survival curves for indicated strains over time plotted as percent survival. (C) Frequency of donor CD45.2 or host CD45.1 total leukocytes (top) and neutrophils (bottom) were assessed in BM chimeras on day 10 following the first TMX injection by FACS. Data are representative of 3-5 independent experiments. Data are represented as mean with S.D. n = 3-5 mice per group, **P < 0.005,***P < 0.005 t-test relative to control.

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Obligate role for Rock1 and Rock2 in adult stem cell viability and function
  • Article
  • Full-text available

March 2023

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121 Reads

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3 Citations

Heliyon

The ability of stem cells to rapidly proliferate and differentiate is integral to the steady-state maintenance of tissues with high turnover such as the blood and intestine. Mutations that alter these processes can cause primary immunodeficiencies, malignancies and defects in barrier function. The Rho-kinases, Rock1 and Rock2, regulate cell shape and cytoskeletal rearrangement, activities essential to mitosis. Here, we use inducible gene targeting to ablate Rock1 and Rock2 in adult mice, and identify an obligate requirement for these enzymes in the preservation of the hematopoietic and gastrointestinal systems. Hematopoietic cell progenitors devoid of Rho-kinases display cell cycle arrest, blocking the differentiation to mature blood lineages. Similarly, these mice exhibit impaired epithelial cell renewal in the small intestine, which is ultimately fatal. Our data reveal a novel role for these kinases in the proliferation and viability of stem cells and their progenitors, which is vital to maintaining the steady-state integrity of these organ systems.

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Disruption of stem cell niche-confined R-spondin 3 expression leads to impaired hematopoiesis

August 2022

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52 Reads

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4 Citations

Blood Advances

Self-renewal and differentiation of stem and progenitor cells are tightly regulated to ensure tissue homeostasis. This regulation is enabled both remotely by systemic circulating cues, such as cytokines and hormones, and locally by various niche-confined factors. R-spondin 3 (RSPO3) is one of the most potent enhancers of Wnt signaling and its expression is usually restricted to the stem cell niche where it provides localized enhancement of Wnt signaling to regulate stem cell expansion and differentiation. Disruption of this niche-confined expression can disturb proper tissue organization and lead to cancers. Here, we investigate the consequences of disrupting the niche restricted expression of RSPO3 in various tissues including the hematopoietic system. We show that normal Rspo3 expression is confined to the perivascular niche in the bone marrow. Induction of increased systemic levels of circulating RSPO3 outside of the niche results in prominent loss of early-B cell progenitors and anemia but surprisingly has no effect on hematopoietic stem cells (HSCs). Using molecular, pharmacological and genetic approaches, we demonstrate that these RSPO3-induced hematopoietic phenotypes are Wnt and RSPO3 dependent and mediated through non-canonical Wnt signaling. Our study highlights a distinct role for a Wnt/RSPO3 signaling axis in the regulation of hematopoiesis, as well as possible challenges related to therapeutic usage of R-spondins for regenerative medicine.


IL-1R1–dependent signaling coordinates epithelial regeneration in response to intestinal damage

May 2021

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295 Reads

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39 Citations

Science Immunology

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1 ⁺ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1–dependent RSPO3 production by GREM1 ⁺ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium–induced colitis. These data demonstrate how IL-1R1–dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.


Gremlin 1 fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues

May 2021

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1,263 Reads

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52 Citations

Nature Immunology

Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell–zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreERT2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1⁺ FRCs. Grem1⁺ FRCs primarily localize at T–B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1⁺ cells marking the endpoint of both trajectories. These findings illuminate a new Grem1⁺ fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs.


Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient

February 2020

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120 Reads

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243 Citations

Cell Stem Cell

Intestinal stem cells (ISCs) are confined to crypt bottoms and their progeny differentiate near crypt-villus junctions. Wnt and bone morphogenic protein (BMP) gradients drive this polarity, and colorectal cancer fundamentally reflects disruption of this homeostatic signaling. However, sub-epithelial sources of crucial agonists and antagonists that organize this BMP gradient remain obscure. Here, we couple whole-mount high-resolution microscopy with ensemble and single-cell RNA sequencing (RNA-seq) to identify three distinct PDGFRA+ mesenchymal cell types. PDGFRA(hi) telocytes are especially abundant at the villus base and provide a BMP reservoir, and we identified a CD81+ PDGFRA(lo) population present just below crypts that secretes the BMP antagonist Gremlin1. These cells, referred to as trophocytes, are sufficient to expand ISCs in vitro without additional trophic support and contribute to ISC maintenance in vivo. This study reveals intestinal mesenchymal structure at fine anatomic, molecular, and functional detail and the cellular basis for a signaling gradient necessary for tissue self-renewal.


A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer

March 2017

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267 Reads

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672 Citations

Nature

Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5+ cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5− cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.


Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function

December 2015

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296 Reads

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216 Citations

Nature

Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.


Citations (9)


... The enteric nervous system exhibits remarkable capacity for regeneration and plasticity, adapting to injury, inflammation, and physiological stress [1][2][3][4] . This plasticity is driven by dynamic interactions between enteric neurons and glial cells, which play integral roles in neuroprotection, tissue homeostasis, and repair [5][6][7][8][9][10][11][12][13] . Enteric glial cells, in particular, act as modulators of neuroactive substances, regulators of inflammatory responses, and contributors to adult neurogenesis [14][15][16][17][18][19][20][21][22] . ...

Reference:

Self-Organizing Assembloids Reveal Enteric Nervous System Dynamics in Gut Homeostasis and Regeneration
Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells
  • Citing Article
  • August 2023

Cell Stem Cell

... Thus, our findings support the coordinated involvement of ROCK1 and ROCK2 in BP regulation. Additionally, in a previous report, blood analyses of ROCK1/ROCK2 knockout mice have shown that several factors, such as glucose, triglyceride, albumin, and BUN, fluctuate [35], suggesting that the two ROCK isoforms also regulate functions in other organs in a coordinated manner. Furthermore, ROCK1 and ROCK2 are widely expressed in the body, but ROCK2 is particularly strongly expressed in some organs such as brain and skeletal muscle [36]. ...

Obligate role for Rock1 and Rock2 in adult stem cell viability and function

Heliyon

... ADGRG1 is expressed in NK cells, gdT cells, and terminal effector T cells in healthy human BM (Supplementary Figure S4A-B) [22,36]. In mouse, Adgrg1 is expressed in hematopoietic stem/progenitor cells (Supplementary Figure S4C-D) [37,38]. Notably, ADGRG1 has also been found to serve as a marker for leukemia stem cells [39]. ...

Disruption of stem cell niche-confined R-spondin 3 expression leads to impaired hematopoiesis

Blood Advances

... This region, due to its exposure to abrasive damage by intestinal contents, facilitates the entry of microbes and immunostimulatory molecules, triggering an inflammatory response associated with tissue repair. Moreover, IL-1-induced inflammation can activate RSPO3 expression in mesenchymal cells and, together with IL-17 activity and matrix metalloproteinases (e.g., MMP2 and MMP3) produced by iCAFs, stimulates angiogenesis and promotes tumor progression [74][75][76]. In this context, the reduction observed in MSI tumors of CAFs expressing CXCL14 and bone morphogenetic proteins (BMPs) is relevant, in contrast to MSS tumors where these CAFs are more abundant. ...

IL-1R1–dependent signaling coordinates epithelial regeneration in response to intestinal damage
  • Citing Article
  • May 2021

Science Immunology

... It has been documented that the excessive ablation of the GREM1 gene in mice precipitates severe intestinal mucosal dysfunction and hematopoietic failure [54,56]. Moreover, studies suggest that GREM1-positive fibroblasts within lymph nodes act as conducive neighbors to dendritic cells, fostering the homeostasis of proximal dendritic cells [81,82]. ...

Gremlin 1 fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues

Nature Immunology

... Several groups have considered FoxL1, PDGFRα, CD34, and Gli1 as intestinal telocyte markers (Shoshkes-Carmel, 2024). Additionally, CD81 has been used in conjunction with the previously described markers to differentiate telocytes from other mesenchymal populations (McCarthy et al., 2020;Kraiczy et al., 2023;Paerregaard et al., 2023;Cadinu et al., 2024). However, on their own, these markers lack specificity. ...

Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient
  • Citing Article
  • February 2020

Cell Stem Cell

... In contrast to the static nature of driver aberrations in CRC, recent data revealed a crucial role for cellular plasticity in metastatic progression. Single cell analyses showed that CRC cells can assume distinct states resembling those in the physiological colon crypt, such as intestinal stem cell (ISC)-like states and differentiated secretory or absorptive states [28,29]. Tumors that recurred with metastases after surgery harbored a subpopulation of CRC cells, which were often undifferentiated and had high migration ability, but lacked stem-like characteristics [30]. ...

A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer
  • Citing Article
  • March 2017

Nature

... Enhanced expression of RSPO3 has been discovered in colon cancer patients, highlighting its potential role in colorectal cancer development. Although RSPO3's overactivation and its oncogenic effects are well-documented, the majority of RSPO-related cancer research focuses on the intestinal tract [34][35][36][37]. Yet, the specific oncogenic role of RSPO3 in the liver remains less understood. ...

Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function
  • Citing Article
  • December 2015

Nature

... The loss of APC abrogates β-catenin destruction, leading to its accumulation, mimicking the constitutive activation of Wnt ligand-mediated signaling [80]. In about 10% of colorectal cancers, the activation of the Wnt pathway follows a different route, through mutations in R-spondins [81]. In another 18% of colorectal cancers, Wnt activation is due to Ring Finger Protein 43 (RNF43) mutations, a protein that usually negatively regulates this pathway [82]. ...

Recurrent R-spondin fusions in colon cancer

Nature