Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis

Nature communications

2023 Jan 20

Pei, F;Ma, L;Jing, J;Feng, J;Yuan, Y;Guo, T;Han, X;Ho, TV;Lei, J;He, J;Zhang, M;Chen, JF;Chai, Y;
PMID: 36670126 | DOI: 10.1038/s41467-023-35977-4

Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components in the homeostasis of tissues such as skin, bone marrow and hematopoietic system. However, how the sensory nerve affects the behavior of MSCs remains largely unknown. Here we show that the sensory nerve is vital for mesenchymal tissue homeostasis and maintenance of MSCs in the continuously growing adult mouse incisor. Loss of sensory innervation leads to mesenchymal disorder and a decrease in MSCs. Mechanistically, FGF1 from the sensory nerve directly acts on MSCs by binding to FGFR1 and activates the mTOR/autophagy axis to sustain MSCs. Modulation of mTOR/autophagy restores the MSCs and rescues the mesenchymal tissue disorder of Fgfr1 mutant mice. Collectively, our study provides insights into the role of sensory nerves in the regulation of MSC homeostasis and the mechanism governing it.

Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia

Nature communications

2022 Sep 17

Lee, SH;Kim, N;Kim, M;Woo, SH;Han, I;Park, J;Kim, K;Park, KS;Kim, K;Shim, D;Park, SE;Zhang, JY;Go, DM;Kim, DY;Yoon, WK;Lee, SP;Chung, J;Kim, KW;Park, JH;Lee, SH;Lee, S;Ann, SJ;Lee, SH;Ahn, HS;Jeong, SC;Kim, TK;Oh, GT;Park, WY;Lee, HO;Choi, JH;
PMID: 36115863 | DOI: 10.1038/s41467-022-33202-2

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.

Loss of Fgf9 in mice leads to pancreatic hypoplasia and asplenia

iScience

2023 Mar 01

Patzek, S;Liu, Z;de la O, S;Chang, S;Byrnes, L;Zhang, X;Ornitz, D;Sneddon, J;
| DOI: 10.1016/j.isci.2023.106500

Pancreatic development requires spatially and temporally controlled expression of growth factors derived from mesenchyme. Here, we report that in mice the secreted factor Fgf9 is expressed principally by mesenchyme and then mesothelium during early development, then subsequently by both mesothelium and rare epithelial cells by E12.5 and onwards. Global knockout of the Fgf9 gene resulted in the reduction of pancreas and stomach size, as well as complete asplenia. The number of early Pdx1+ pancreatic progenitors was reduced at E10.5, as was proliferation of mesenchyme at E11.5. Although loss of Fgf9 did not interfere with differentiation of later epithelial lineages, single-cell RNA-Sequencing identified transcriptional programs perturbed upon loss of Fgf9 during pancreatic development, including loss of the transcription factor Barx1. Lastly, we identified conserved expression patterns of FGF9 and receptors in human fetal pancreas, suggesting that FGF9 expressed by pancreatic mesenchyme may similarly affect the development of the human pancreas.

Smooth muscle contributes to the development and function of a layered intestinal stem cell niche

Developmental cell

2023 Mar 08

McCarthy, N;Tie, G;Madha, S;He, R;Kraiczy, J;Maglieri, A;Shivdasani, RA;
PMID: 36924771 | DOI: 10.1016/j.devcel.2023.02.012

Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types. Niche functions refine during postnatal crypt morphogenesis, in part to oppose the dense aggregation of differentiation-promoting BMP+ sub-epithelial myofibroblasts at crypt-villus junctions. Muscularis mucosae, a specialized muscle layer, first appears during this period and supplements neighboring RSPO and BMPi sources. Components of this developing niche are conserved in human fetuses. The in vivo ablation of mouse postnatal smooth muscle increases BMP signaling activity, potently limiting a pre-weaning burst of crypt fission. Thus, distinct and progressively specialized mesenchymal cells together create the milieu that is required to propagate crypts during rapid organ growth and to sustain adult ISCs.

Generation of the organotypic kidney structure by integrating pluripotent stem cell-derived renal stroma

Nature communications

2022 Feb 01

Tanigawa, S;Tanaka, E;Miike, K;Ohmori, T;Inoue, D;Cai, CL;Taguchi, A;Kobayashi, A;Nishinakamura, R;
PMID: 35105870 | DOI: 10.1038/s41467-022-28226-7

Organs consist of the parenchyma and stroma, the latter of which coordinates the generation of organotypic structures. Despite recent advances in organoid technology, induction of organ-specific stroma and recapitulation of complex organ configurations from pluripotent stem cells (PSCs) have remained challenging. By elucidating the in vivo molecular features of the renal stromal lineage at a single-cell resolution level, we herein establish an in vitro induction protocol for stromal progenitors (SPs) from mouse PSCs. When the induced SPs are assembled with two differentially induced parenchymal progenitors (nephron progenitors and ureteric buds), the completely PSC-derived organoids reproduce the complex kidney structure, with multiple types of stromal cells distributed along differentiating nephrons and branching ureteric buds. Thus, integration of PSC-derived lineage-specific stroma into parenchymal organoids will pave the way toward recapitulation of the organotypic architecture and functions.

Single-Cell RNA Sequencing Analysis Reveals Sequential Cell Fate Transition during Human Spermatogenesis

Cell Stem Cell

2018 Aug 30

Wang M, Liu X, Chang G, Chen Y, An G, Yan L, Gao S, Xu Y, Cui Y, Dong J, Chen Y, Fan X, Hu Y, Song K, Zhu X, Gao Y, Yao Z, Bian S, Hou Y, Lu J, Wang R, Fan Y, Lian Y, Tang W, Wang Y, Liu J, Zhao L, Wang L, Liu Z, Yuan R, Shi Y, Hu B, Ren X, Tang F, Zhao X
PMID: - | DOI: 10.1016/j.stem.2018.08.007

Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscapes of human spermatogenesis remain unknown. Here, we performed single-cell RNA sequencing(scRNA-seq) analysis for 2,854 testicular cells from donors with normal spermatogenesis and 174 testicular cells from one nonobstructive azoospermia (NOA) donor. A hierarchical model was established, which was characterized by the sequential and stepwise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes. Further analysis identified several stage-specific marker genes of human germ cells, such as HMGA1, PIWIL4, TEX29, SCML1, and CCDC112. Moreover, we identified altered gene expression patterns in the testicular somatic cells of one NOA patient via scRNA-seq analysis, paving the way for further diagnosis of male infertility. Our work allows for the reconstruction of transcriptional programs inherent to sequential cell fate transition during human spermatogenesis and has implications for deciphering male-related reproductive disorders.

Shared and distinct transcriptomic cell types across neocortical areas.

Nature. 2018 Nov;563(7729):72-78.

2018 Oct 31

Tasic B, Yao Z, Graybuck LT, Smith KA, Nguyen TN, Bertagnolli D, Goldy J, Garren E, Economo MN, Viswanathan S, Penn O, Bakken T, Menon V, Miller J, Fong O, Hirokawa KE, Lathia K, Rimorin C, Tieu M, Larsen R, Casper T, Barkan E, Kroll M, Parry S, Shapovalova NV, Hirschstein D, Pendergraft J, Sullivan HA, Kim TK, Szafer A, Dee N, Groblewski P, Wickersham I, Cetin A, Harris JA, Levi BP, Sunkin SM, Madisen L, Daigle TL, Looger L, Bernard A, Phillips J, Lein E, Hawrylycz M, Svoboda K, Jones AR, Koch C, Zeng H.
PMID: 30382198 | DOI: 10.1038/s41586-018-0654-5

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (gamma-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Spiny mice activate unique transcriptional programs after severe kidney injury regenerating organ function without fibrosis

iScience

2021 Nov 01

Okamura, D;Brewer, C;Wakenight, P;Bahrami, N;Bernardi, K;Tran, A;Olson, J;Shi, X;Yeh, S;Piliponsky, A;Collins, S;Nguyen, E;Timms, A;MacDonald, J;Bammler, T;Nelson, B;Millen, K;Beier, D;Majesky, M;
| DOI: 10.1016/j.isci.2021.103269

Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice (Acomys) are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the Acomys genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney.

Shared and distinct transcriptomic cell types across neocortical areas.

Nature.

2018 Oct 31

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

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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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