Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas

Casteele, Mark Van de; Leuckx, Gunter; Baeyens, Luc; Cai, Ying; Yuchi, Yixing; Coppens, Violette; Groef, Sofie De; Eriksson, Maria; Svensson, Christoffer; Ahlgren, Ulf; Ahnfelt-Rønne, Jonas; Madsen, Ole; Waisman, Ari; Dor, Yuval; Jensen, Jan; Heimberg, Henry

doi:10.1038/cddis.2013.52

Cited by 95 publications

(99 citation statements)

References 27 publications

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“…In contrast, we concluded that neogenesis was insignificant in PDL pancreases because Ngn3 transcript levels were below 0.2-fold of the normalized level seen in the duodenal tissue (6). The hypothesis that the number of Ngn3 + transitional intermediate cells or the individual Ngn3 level per cell is rate-limiting for b-cell neogenesis should be testable.…”

Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 85%

“…We found that the global Ngn3 mRNA level detected by quantitative RT-PCR in the PDL tail showed a strong correlation with 1) number of b-cells derived from Ngn3 + cells; 2) number of islets that showed dilution of prelabeled b-cells by unlabeled b-cells at 14 days post-PDL, particularly small ones containing 20 or fewer b-cells; and 3) the overall dilution of prelabeled b-cells scored at 35 days post-PDL (6). Together, these data support the idea that precursors of at least some new b-cells derived under PDL context are from a non-b-cell source(s).…”

Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 94%

“…Some authors suggest that in PDL, determining the fractional b-cell volume per unit of pancreatic tissue (excluding any fibrotic, adipocyte, or other tissue) is more accurate than b-cell mass, which first requires a determination of mass (18). However, even when using the fractional total b-cell volume as a metric, some laboratories observe quantifiable increases in the b-cell pool under PDL (4,6,10), while others do not (18)(19)(20).…”

Section: Increased B-cell Formation In Pdl Pancreasmentioning

confidence: 99%

“…Because we hypothesized that the appearance of new b-cells moves through an intermediate or transitional state associated with the re-expression, or increased expression of Ngn3, we sought circumstantial evidence for this idea (6). We found that the global Ngn3 mRNA level detected by quantitative RT-PCR in the PDL tail showed a strong correlation with 1) number of b-cells derived from Ngn3 + cells; 2) number of islets that showed dilution of prelabeled b-cells by unlabeled b-cells at 14 days post-PDL, particularly small ones containing 20 or fewer b-cells; and 3) the overall dilution of prelabeled b-cells scored at 35 days post-PDL (6).…”

Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 99%

“…Unfortunately, discrepancies among PDL studies have led to discouragement about the validity of this injury model as a valid analytical tool to study the ability of b-cells to return to a proliferative condition or increase their cellcycling rate or for non-b-cells to undergo redirection toward a b and/or other endocrine state (4)(5)(6)12,29). Although some of this uncertainty pertains to the experimental variability described, it is important to point out that appropriate application of rigorous lineage-tracing tools could help sort through the apparent confusion.…”

Section: Exocrine Cells As a Source For New B-cells In Pdl Pancreasmentioning

confidence: 99%

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Partial Duct Ligation: β-Cell Proliferation and Beyond

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Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 85%

Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 94%

Section: Increased B-cell Formation In Pdl Pancreasmentioning

confidence: 99%

Section: Ngn3 Transcript Level and B-cell Neogenesismentioning

confidence: 99%

Section: Exocrine Cells As a Source For New B-cells In Pdl Pancreasmentioning

confidence: 99%

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Partial Duct Ligation: β-Cell Proliferation and Beyond

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Quantifying the Dynamics of Hematopoiesis by In Vivo IdU Pulse‐Chase, Mass Cytometry, and Mathematical Modeling

2019

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We present a new method to directly quantify the dynamics of differentiation of multiple cellular subsets in unperturbed mice. We combine a pulse-chase protocol of IdU injections with subsequent analysis by mass cytometry (CyTOF), and mathematical modeling of the IdU dynamics. Measurements by CyTOF allow for a wide range of cells to be analyzed at once, due to the availability of a large staining panel without the complication of fluorescence spill-over. These are also compatible with direct detection of integrated iodine signal, with minimal impact on immunophenotyping based on surface markers. Mathematical modeling beyond a binary classification of surface marker abundance allows for a continuum of cellular states as the cells transition from one state to another. Thus, we present a complete and robust method for directly quantifying differentiation at the systemic level, allowing for system-wide comparisons between different mouse strains and/or experimental conditions.

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Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas

et al. 2015

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Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (M s)were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident M types, designated MHC-II lo and MHC-II hi M s, the latter being predominant. MHC-II lo and MHC-II hi pancreas M s differed at the molecular level, with MHC-II lo M s being more M2-activated. After PDL, there was an early surge of Ly6C hi monocyte infiltration in the pancreas, followed by a transient MHC-II lo M peak and ultimately a restoration of the MHC-II hi M -dominated steadystate equilibrium. These intricate M dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local M proliferation. Functionally, MHC-II lo M s were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue M s, rather than Ly6C hi monocyte-derived M s, contributed to β-cell proliferation. Together, our study fully characterizes the M subsets in the pancreas and clarifies the complex dynamics of M s after PDL injury.Keywords: M activation r M heterogeneity r M proliferation r Pancreas inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Harry Heimberg and Prof. Jo A. Van Ginderachter e-mail: harry.heimberg@vub.ac.be e-mail: jvangind@vub.ac.be * These authors contributed equally to this study as first co-authors. * * These authors contributed equally to this study as senior co-authors.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1482-1493 Innate immunity 1483Introduction M s display a tremendous plasticity in vivo depending on their microenvironment. Their activation status has been described using the conceptual framework of M1 (classical) and M2 (alternative) activation [1], although this model oversimplifies their true plasticity. In addition to their role as immune cells, the trophic role of M s during development, tissue repair, and regeneration is becoming increasingly appreciated [1,2]. Hence, efforts are being made to dissect specialized M subpopulations and to trace their origin in situations of sterile inflammation. Although tissueresident M s were traditionally believed to originate from bloodborne monocytes, recent evidence shows that such M s develop prenatally from dedicated precursors [3,4]. During adulthood, the pool of tissue-resident M s is maintained by low-level proliferation under steady-state [5] and can expand by enhanced in situ proliferation during pathologies [6][7][8][9]. Moreover, during sterile inflammat...

show abstract

Neurogenin 3+ cells contribute to β-cell neogenesis and proliferation in injured adult mouse pancreas

Cited by 95 publications

References 27 publications

Partial Duct Ligation: β-Cell Proliferation and Beyond

Partial Duct Ligation: β-Cell Proliferation and Beyond

Quantifying the Dynamics of Hematopoiesis by In Vivo IdU Pulse‐Chase, Mass Cytometry, and Mathematical Modeling

Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas

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