Faculty Opinions recommendation of Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury.

Abstract Background It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress. Objective Our objective was to determine whether open, sc fat biopsies cause ER stress. Approach Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes. Results mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not. Conclusion Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.

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Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity

AJP Renal Physiology ◽

10.1152/ajprenal.00261.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. F262-F270 ◽

Cited By ~ 11

Author(s):

Hae-Seong Yoon ◽

Terrence J. Monks ◽

Jeffrey I. Everitt ◽

Cheryl L. Walker ◽

Serrine S. Lau

Keyword(s):

Cell Proliferation ◽

Tissue Injury ◽

Tumor Development ◽

Suppressor Gene ◽

Tumor Formation ◽

Renal Tumors ◽

Outer Stripe ◽

Acute Tissue Injury ◽

Cell Cycle Deregulation ◽

Erk Activity

Although 2,3,5-tris-(glutathion- S-yl)hydroquinone (TGHQ; 2.5 μmol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type ( Tsc2+/+ ) and mutant Eker rats ( Tsc2 EK/+), only TGHQ-treated Tsc2 EK/+ rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2 EK/+ rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

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Perivascular cells support folliculogenesis in the developing ovary

10.1101/2021.04.26.441453 ◽

2021 ◽

Author(s):

Shuyun Li ◽

Bidur Bhandary ◽

Tony DeFalco

Keyword(s):

Granulosa Cells ◽

Lineage Tracing ◽

Female Gonad ◽

Perivascular Cells ◽

Cell Specification ◽

Perivascular Cell ◽

Culture Techniques ◽

Ovarian Differentiation ◽

Multipotent Progenitors ◽

Cellular Source

AbstractGranulosa cells, supporting cells of the ovary, are essential for ovarian differentiation by providing a nurturing environment for oogenesis. Sufficient numbers of granulosa cells are vital for establishment of follicles and the oocyte reserve; therefore, identifying the cellular source from which granulosa cells are derived is critical for understanding basic ovarian biology. One cell type that has received little attention in this field is the perivascular cell. Here we use lineage tracing and organ culture techniques in mice to identify ovarian Nestin+ perivascular cells as multipotent progenitors that contribute to granulosa, thecal, and pericyte lineages. Maintenance of these progenitors was dependent on vascular-mesenchymal Notch signaling. Ablation of postnatal Nestin+ cells resulted in a disruption of granulosa cell specification and an increased incidence of polyovular ovarian follicles, thus uncovering key roles for vasculature in ovarian differentiation. These findings may provide new insights into the origins of female gonad dysgenesis and infertility.

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Mesenchymal stromal cell therapeutic potency is dependent upon viability, route of delivery, and immune match

Blood Advances ◽

10.1182/bloodadvances.2020001711 ◽

2020 ◽

Vol 4 (9) ◽

pp. 1987-1997 ◽

Cited By ~ 5

Author(s):

Jayeeta Giri ◽

Jacques Galipeau

Keyword(s):

Clinical Outcomes ◽

Animal Studies ◽

Tissue Injury ◽

Pharmaceutical Product ◽

Clinical Indication ◽

Functional Fitness ◽

Substantial Impact ◽

Clinical Endpoints ◽

Acute Tissue Injury

Abstract Culture-adapted bone marrow mesenchymal stromal cells (MSCs) deploy paracrine anti-inflammatory and tissue regenerative functionalities that can be harnessed as a living cell pharmaceutical product. Independent of clinical indication, a near majority of human clinical trials administer MSC IV, often with an allogeneic MSC cell product immediately after thawing from cryostorage. Despite hundreds of studies in a wide assortment of inflammatory, degenerative, and acute tissue injury syndromes, human clinical outcomes often fail to mirror promising rigorously conducted preclinical animal studies. Using a mouse model of toxic colitis, we demonstrate that replication fit MSCs harvested in log phase of growth have substantial impact on colitis clinical and pathologic endpoints when delivered subcutaneously or intraperitoneally, whereas the maximum tolerated IV bolus dosing failed to do so. We also demonstrate that heat-inactivated MSCs lose all therapeutic utility and the observation is mirrored by use of viable MSC administered immediately postthaw from cryostorage. Using luciferase transgenic MSC as donor cells, we demonstrate that transient in vivo engraftment is severely compromised when MSCs are dead or thawed and further demonstrate that MSC redosing is feasible in relapsing colitis, but only syngeneic MSCs lead to sustained improvement of clinical endpoints. These data support the notion that pharmaceutical potency of MSC requires viability and functional fitness. Reciprocally, IV administration of thawed MSC products may be biased against positive clinical outcomes for treatment of colitis and that extravascular administration of syngeneic, fit MSCs allows for effect in a recurrent therapy model.

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Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress

Endocrinology ◽

10.1210/endo.150.12.9995 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5651-5651

Author(s):

Guenther Boden ◽

Matthew Silviera ◽

Brian Smith ◽

Peter Cheung ◽

Carol Homko

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Tissue Injury ◽

Subcutaneous Fat ◽

Acute Tissue Injury

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Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1013004108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 179-184 ◽

Cited By ~ 337

Author(s):

Robert K. Montgomery ◽

Diana L. Carlone ◽

Camilla A. Richmond ◽

Loredana Farilla ◽

Mariette E. G. Kranendonk ◽

...

Keyword(s):

Stem Cells ◽

Reverse Transcriptase ◽

Tissue Injury ◽

Cell Types ◽

Lineage Tracing ◽

Intestinal Stem Cells ◽

Intestinal Cell ◽

Stem Cell Population ◽

Telomerase Reverse Transcriptase

The intestinal epithelium is maintained by a population of rapidly cycling (Lgr5+) intestinal stem cells (ISCs). It has been postulated, however, that slowly cycling ISCs must also be present in the intestine to protect the genome from accumulating deleterious mutations and to allow for a response to tissue injury. Here, we identify a subpopulation of slowly cycling ISCs marked by mouse telomerase reverse transcriptase (mTert) expression that can give rise to Lgr5+ cells. mTert-expressing cells distribute in a pattern along the crypt–villus axis similar to long-term label-retaining cells (LRCs) and are resistant to tissue injury. Lineage-tracing studies demonstrate that mTert+ cells give rise to all differentiated intestinal cell types, persist long term, and contribute to the regenerative response following injury. Consistent with other highly regenerative tissues, our results demonstrate that a slowly cycling stem cell population exists within the intestine.

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Identification of a basal stem cell subpopulation in the prostate via functional, lineage tracing and single-cell RNA-seq analyses

10.1101/601872 ◽

2019 ◽

Cited By ~ 1

Author(s):

Xue Wang ◽

Haibo Xu ◽

Chaping Cheng ◽

Zhongzhong Ji ◽

Huifang Zhao ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Epithelial Cells ◽

Single Cell ◽

Basal Cell ◽

Lineage Tracing ◽

Cell Subpopulation ◽

Basal Cells ◽

Mesenchymal Transition ◽

Genetic Ablation

AbstractThe basal cell compartment in many epithelial tissues such as the prostate, bladder, and mammary gland are generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb is exclusively expressed in a prostate basal cell subpopulation based on both immunocytochemical and cell lineage tracing analysis. The Zeb1+prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures with all three epithelial cell types at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single cell transcriptomic analysis of over 9000 mouse prostate basal cells, we find that Zeb1+basal cell subset shares gene expression signatures with both epithelial and mesenchymal cells and stands out uniquely among all the basal cell clusters. Moreover, Zeb1+epithelial cells can be detected in mouse and clinical samples of prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis.

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