Ectopic stem cell niches sustain rainbow trout (Oncorhynchus mykiss) intestine absorptive capacity when challenged with a plant protein-rich diet

Aquaculture

2023 Feb 01

Verdile, N;Cardinaletti, G;Faccenda, F;Brevini, T;Gandolfi, F;Tibaldi, E;
| DOI: 10.1016/j.aquaculture.2022.739031

To develop more sustainable feed formulations, it is important to assess in detail their effect on gut function and health. We previously described the specific organization of the epithelial and stromal components of the intestinal stem cell niche (ISCN), in rainbow trout (RT) under actual farming conditions. In the present work, we used our previous observation, for performing a comparative analysis between a control diet (CF) and an experimental vegetable-based diet (CV) under a new perspective. We correlated diet-induced changes of the morphology and the absorptive capability of the RT mucosa with modifications of the ISCN. Histological analysis confirmed that CV diet caused a mucosa remodeling, characterized by the generation of accessory branches sprouting from the middle of the proximal intestine folds, determining a significant increase of the luminal surface. The newly-formed structures showed positivity for PepT1, Sglt-1, and Fabp2 indicating their active role in small molecule absorption. However, the cells lining the base of the new branches expressed both epithelial (sox9) and stromal (pdgfrα and foxl1) stem cell markers, rather than the expected markers of fully differentiated cells. Our results suggest that a nutritional challenge results in the formation of an ectopic ISNC at the middle of the intestinal folds that sustains the formation of functional collateral branches, presumably to compensate for the reduced intestinal absorption. Overall, these data highlight, for the first time, the plasticity of the ISCN and its possible role in compensating intestinal functions in response to challenging conditions.

Glial progenitor heterogeneity and key regulators revealed by single-cell RNA sequencing provide insight to regeneration in spinal cord injury

Cell reports

2023 May 06

Wei, H;Wu, X;Withrow, J;Cuevas-Diaz Duran, R;Singh, S;Chaboub, LS;Rakshit, J;Mejia, J;Rolfe, A;Herrera, JJ;Horner, PJ;Wu, JQ;
PMID: 37149868 | DOI: 10.1016/j.celrep.2023.112486

Recent studies have revealed the heterogeneous nature of astrocytes; however, how diverse constituents of astrocyte-lineage cells are regulated in adult spinal cord after injury and contribute to regeneration remains elusive. We perform single-cell RNA sequencing of GFAP-expressing cells from sub-chronic spinal cord injury models and identify and compare with the subpopulations in acute-stage data. We find subpopulations with distinct functional enrichment and their identities defined by subpopulation-specific transcription factors and regulons. Immunohistochemistry, RNAscope experiments, and quantification by stereology verify the molecular signature, location, and morphology of potential resident neural progenitors or neural stem cells in the adult spinal cord before and after injury and uncover the populations of the intermediate cells enriched in neuronal genes that could potentially transition into other subpopulations. This study has expanded the knowledge of the heterogeneity and cell state transition of glial progenitors in adult spinal cord before and after injury.

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

Heliyon

2023 Mar 01

Sambandam, A;Storm, E;Tauc, H;Hackney, JA;Garfield, D;Caplazi, P;Liu, J;Zhang, J;Zhang, H;Duggan, J;Jeet, S;Gierke, S;Chang, P;Wu, X;Newman, R;Tam, L;Alcantar, T;Wang, L;Roose-Girma, M;Modrusan, Z;Lee, WP;Jasper, H;de Sauvage, F;Pappu, R;
PMID: 36950615 | DOI: 10.1016/j.heliyon.2023.e14238

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.

Dysregulated transforming growth factor-beta mediates early bone marrow dysfunction in diabetes

Communications biology

2022 Oct 28

Kum, JJY;Howlett, CJ;Khan, ZA;
PMID: 36307522 | DOI: 10.1038/s42003-022-04112-2

Diabetes affects select organs such as the eyes, kidney, heart, and brain. Our recent studies show that diabetes also enhances adipogenesis in the bone marrow and reduces the number of marrow-resident vascular regenerative stem cells. In the current study, we have performed a detailed spatio-temporal examination to identify the early changes that are induced by diabetes in the bone marrow. Here we show that short-term diabetes causes structural and molecular changes in the marrow, including enhanced adipogenesis in tibiae of mice, prior to stem cell depletion. This enhanced adipogenesis was associated with suppressed transforming growth factor-beta (TGFB) signaling. Using human bone marrow-derived mesenchymal progenitor cells, we show that TGFB pathway suppresses adipogenic differentiation through TGFB-activated kinase 1 (TAK1). These findings may inform the development of novel therapeutic targets for patients with diabetes to restore regenerative stem cell function.

Dietary suppression of MHC class II expression in intestinal epithelial cells enhances intestinal tumorigenesis

Cell stem cell

2021 Sep 15

Beyaz, S;Chung, C;Mou, H;Bauer-Rowe, KE;Xifaras, ME;Ergin, I;Dohnalova, L;Biton, M;Shekhar, K;Eskiocak, O;Papciak, K;Ozler, K;Almeqdadi, M;Yueh, B;Fein, M;Annamalai, D;Valle-Encinas, E;Erdemir, A;Dogum, K;Shah, V;Alici-Garipcan, A;Meyer, HV;Özata, DM;Elinav, E;Kucukural, A;Kumar, P;McAleer, JP;Fox, JG;Thaiss, CA;Regev, A;Roper, J;Orkin, SH;Yilmaz, ÖH;
PMID: 34529935 | DOI: 10.1016/j.stem.2021.08.007

Little is known about how interactions of diet, intestinal stem cells (ISCs), and immune cells affect early-stage intestinal tumorigenesis. We show that a high-fat diet (HFD) reduces the expression of the major histocompatibility complex class II (MHC class II) genes in intestinal epithelial cells, including ISCs. This decline in epithelial MHC class II expression in a HFD correlates with reduced intestinal microbiome diversity. Microbial community transfer experiments suggest that epithelial MHC class II expression is regulated by intestinal flora. Mechanistically, pattern recognition receptor (PRR) and interferon-gamma (IFNγ) signaling regulates epithelial MHC class II expression. MHC class II-negative (MHC-II-) ISCs exhibit greater tumor-initiating capacity than their MHC class II-positive (MHC-II+) counterparts upon loss of the tumor suppressor Apc coupled with a HFD, suggesting a role for epithelial MHC class II-mediated immune surveillance in suppressing tumorigenesis. ISC-specific genetic ablation of MHC class II increases tumor burden cell autonomously. Thus, HFD perturbs a microbiome-stem cell-immune cell interaction that contributes to tumor initiation in the intestine.

KIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration

Nature communications

2023 Apr 10

Chen, L;Shi, K;Ditzel, N;Qiu, W;Figeac, F;Nielsen, LHD;Tencerova, M;Kowal, JM;Ding, M;Andreasen, CM;Andersen, TL;Kassem, M;
PMID: 37037828 | DOI: 10.1038/s41467-023-37651-1

Upon transplantation, skeletal stem cells (also known as bone marrow stromal or mesenchymal stem cells) can regulate bone regeneration by producing secreted factors. Here, we identify KIAA1199 as a bone marrow stromal cell-secreted factor in vitro and in vivo. KIAA1199 plasma levels of patients positively correlate with osteoporotic fracture risk and expression levels of KIAA1199 in patient bone marrow stromal cells negatively correlates with their osteogenic differentiation potential. KIAA1199-deficient bone marrow stromal cells exhibit enhanced osteoblast differentiation in vitro and ectopic bone formation in vivo. Consistently, KIAA1199 knockout mice display increased bone mass and biomechanical strength, as well as an increased bone formation rate. They also exhibit accelerated healing of surgically generated bone defects and are protected from ovariectomy-induced bone loss. Mechanistically, KIAA1199 regulates osteogenesis by inhibiting the production of osteopontin by osteoblasts, via integrin-mediated AKT and ERK-MAPK intracellular signaling. Thus, KIAA1199 is a regulator of osteoblast differentiation and bone regeneration and could be targeted for the treatment or management of low bone mass conditions.

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

Cell reports

2023 Apr 27

Cardenas-Diaz, FL;Liberti, DC;Leach, JP;Babu, A;Barasch, J;Shen, T;Diaz-Miranda, MA;Zhou, S;Ying, Y;Callaway, DA;Morley, MP;Morrisey, EE;
PMID: 37119134 | DOI: 10.1016/j.celrep.2023.112451

Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single-cell transcriptomics, software-guided segmentation of tissue damage, and in vivo mouse lineage tracing, we identified the grainyhead transcription factor cellular promoter 2-like 1 (Tfcp2l1) as a regulator of this regenerative process. Tfcp2l1 loss in adult AT2 cells inhibits self-renewal and enhances AT2-AT1 differentiation during tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute injury phase. Tfcp2l1 temporally regulates AT2 self-renewal and differentiation in alveolar regions undergoing active regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics across the AT2-AT1 differentiation and restricts the inflammatory program in murine AT2 cells. Organoid modeling shows that Tfcp2l1 regulation of interleukin-1 (IL-1) receptor expression controlled these cell fate dynamics. These findings highlight the critical role Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation during alveolar regeneration.

IRX5 promotes DNA damage repair and activation of hair follicle stem cells

Stem cell reports

2023 Apr 07

Chen, JK;Wiedemann, J;Nguyen, L;Lin, Z;Tahir, M;Hui, CC;Plikus, MV;Andersen, B;
PMID: 37084727 | DOI: 10.1016/j.stemcr.2023.03.013

The molecular mechanisms allowing hair follicles to periodically activate their stem cells (HFSCs) are incompletely characterized. Here, we identify the transcription factor IRX5 as a promoter of HFSC activation. Irx5-/- mice have delayed anagen onset, with increased DNA damage and diminished HFSC proliferation. Open chromatin regions form near cell cycle progression and DNA damage repair genes in Irx5-/- HFSCs. DNA damage repair factor BRCA1 is an IRX5 downstream target. Inhibition of FGF kinase signaling partially rescues the anagen delay in Irx5-/- mice, suggesting that the Irx5-/- HFSC quiescent phenotype is partly due to failure to suppress Fgf18 expression. Interfollicular epidermal stem cells also show decreased proliferation and increased DNA damage in Irx5-/-mice. Consistent with a role for IRX5 as a promoter of DNA damage repair, we find that IRX genes are upregulated in many cancer types and that there is a correlation between IRX5 and BRCA1 expression in breast cancer.

Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir

Immunity

2023 Feb 16

Wang, C;Hyams, B;Allen, NC;Cautivo, K;Monahan, K;Zhou, M;Dahlgren, MW;Lizama, CO;Matthay, M;Wolters, P;Molofsky, AB;Peng, T;
PMID: 36822205 | DOI: 10.1016/j.immuni.2023.01.032

Aberrant tissue-immune interactions are the hallmark of diverse chronic lung diseases. Here, we sought to define these interactions in emphysema, a progressive disease characterized by infectious exacerbations and loss of alveolar epithelium. Single-cell analysis of human emphysema lungs revealed the expansion of tissue-resident lymphocytes (TRLs). Murine studies identified a stromal niche for TRLs that expresses Hhip, a disease-variant gene downregulated in emphysema. Stromal-specific deletion of Hhip induced the topographic expansion of TRLs in the lung that was mediated by a hyperactive hedgehog-IL-7 axis. 3D immune-stem cell organoids and animal models of viral exacerbations demonstrated that expanded TRLs suppressed alveolar stem cell growth through interferon gamma (IFNγ). Finally, we uncovered an IFNγ-sensitive subset of human alveolar stem cells that was preferentially lost in emphysema. Thus, we delineate a stromal-lymphocyte-epithelial stem cell axis in the lung that is modified by a disease-variant gene and confers host susceptibility to emphysema.

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice

Aging cell

2023 Feb 16

Sun, Q;Ma, L;Qiao, J;Wang, X;Li, J;Wang, Y;Tan, A;Ye, Z;Wu, Y;Xi, J;Kang, J;
PMID: 36797653 | DOI: 10.1111/acel.13794

Hippocampal neural stem cell (NSC) proliferation is known to decline with age, which is closely linked to learning and memory impairments. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes. The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.

Prominin-1 promotes restitution of the murine extrahepatic biliary luminal epithelium following cholestatic liver injury

Hepatology communications

2023 Jan 20

Zhong, A;Short, C;Xu, J;Fernandez, GE;Malkoff, N;Noriega, N;Yeo, T;Wang, L;Mavila, N;Asahina, K;Wang, KS;
PMID: 36662671 | DOI: 10.1097/HC9.0000000000000018

Restitution of the extrahepatic biliary luminal epithelium in cholangiopathies is poorly understood. Prominin-1 (Prom1) is a key component of epithelial ciliary body of stem/progenitor cells. Given that intrahepatic Prom1-expressing progenitor cells undergo cholangiocyte differentiation, we hypothesized that Prom1 may promote restitution of the extrahepatic bile duct (EHBD) epithelium following injury.Utilizing various murine biliary injury models, we identified Prom1-expressing cells in the peribiliary glands of the EHBD. These Prom1-expressing cells are progenitor cells which give rise to cholangiocytes as part of the normal maintenance of the EHBD epithelium. Following injury, these cells proliferate significantly more rapidly to re-populate the biliary luminal epithelium. Null mutation of Prom1 leads to significantly >10-fold dilated peribiliary glands following rhesus rotavirus-mediated biliary injury. Cultured organoids derived from Prom1 knockout mice are comprised of biliary progenitor cells with altered apical-basal cellular polarity, significantly fewer and shorter cilia, and decreased organoid proliferation dynamics consistent with impaired cell motility.We, therefore, conclude that Prom1 is involved in biliary epithelial restitution following biliary injury in part through its role in supporting cell polarity.

Plap-1 lineage tracing and single-cell transcriptomics reveal cellular dynamics in the periodontal ligament

Development (Cambridge, England)

2022 Oct 01

Iwayama, T;Iwashita, M;Miyashita, K;Sakashita, H;Matsumoto, S;Tomita, K;Bhongsatiern, P;Kitayama, T;Ikegami, K;Shimbo, T;Tamai, K;Murayama, MA;Ogawa, S;Iwakura, Y;Yamada, S;Olson, LE;Takedachi, M;Murakami, S;
PMID: 36245218 | DOI: 10.1242/dev.201203

Periodontal tissue supports teeth in the alveolar bone socket via fibrous attachment of the periodontal ligament (PDL). The PDL contains periodontal fibroblasts and stem/progenitor cells, collectively known as PDL cells (PDLCs), on top of osteoblasts and cementoblasts on the surface of alveolar bone and cementum, respectively. However, the characteristics and lineage hierarchy of each cell type remain poorly defined. This study identified periodontal ligament associated protein-1 (Plap-1) as a PDL-specific extracellular matrix protein. We generated knock-in mice expressing CreERT2 and GFP specifically in Plap-1-positive PDLCs. Genetic lineage tracing confirmed the long-standing hypothesis that PDLCs differentiate into osteoblasts and cementoblasts. A PDL single-cell atlas defined cementoblasts and osteoblasts as Plap-1-Ibsp+Sparcl1+ and Plap-1-Ibsp+Col11a2+, respectively. Other populations, such as Nes+ mural cells, S100B+ Schwann cells, and other non-stromal cells, were also identified. RNA velocity analysis suggested that a Plap-1highLy6a+ cell population was the source of PDLCs. Lineage tracing of Plap-1+ PDLCs during periodontal injury showed periodontal tissue regeneration by PDLCs. Our study defines diverse cell populations in PDL and clarifies the role of PDLCs in periodontal tissue homeostasis and repair.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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