Compartmentalized organization: a common and required feature of stem cell niches?

Greco, Valentina; Guo, Shangqin

doi:10.1242/dev.041103

Cited by 65 publications

(74 citation statements)

References 82 publications

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“…Insulation from inductive signals would ensure the maintenance of a progenitor cell pool for continued rounds of nephron differentiation. Compartmentalization, which is a feature of numerous progenitor cell niches in the adult, prevents premature exhaustion of the highest order progenitors, and it is an intriguing possibility that progenitor cell organization in the developing kidney might fit this paradigm (Greco and Guo, 2010).…”

Section: Introductionmentioning

confidence: 99%

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

et al. 2011

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SUMMARYRecent studies indicate that nephron progenitor cells of the embryonic kidney are arranged in a series of compartments of an increasing state of differentiation. The earliest progenitor compartment, distinguished by expression of CITED1, possesses greater capacity for renewal and differentiation than later compartments. Signaling events governing progression of nephron progenitor cells through stages of increasing differentiation are poorly understood, and their elucidation will provide key insights into normal and dysregulated nephrogenesis, as well as into regenerative processes that follow kidney injury. In this study, we found that the mouse CITED1 + progenitor compartment is maintained in response to receptor tyrosine kinase (RTK) ligands that activate both FGF and EGF receptors. This RTK signaling function is dependent on RAS and PI3K signaling but not ERK. In vivo, RAS inactivation by expression of sprouty 1 (Spry1) in CITED1 + nephron progenitors results in loss of characteristic molecular marker expression and in increased death of progenitor cells. Lineage tracing shows that surviving Spry1-expressing progenitor cells are impaired in their subsequent epithelial differentiation, infrequently contributing to epithelial structures. These findings demonstrate that the survival and developmental potential of cells in the earliest embryonic nephron progenitor cell compartment are dependent on FGF/EGF signaling through RAS.

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Section: Introductionmentioning

confidence: 99%

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

et al. 2011

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“…It has been suggested that Bmi1 and Lgr5 mark an overlapping and possibly identical or redundant population of ISCs (5,7,9); however, no direct exploration of their functional similarities and differences has been performed. Further, it is unknown how Bmi1 + and Lgr5 + ISCs relate to a proposed model in which the intestine differentially uses an actively cycling ISC population during homeostasis and a distinct quiescent, injury-induced ISC population (10,11) …”

mentioning

confidence: 99%

The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

Yan¹,

Chia²,

Li³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

721

810

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The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1 + ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1 + ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5 + ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.R-spondin | Dickkopf-1 | intestinal regeneration T he G protein-coupled receptor Lgr5 and the Polycomb group protein Bmi1 are two recently described molecular markers of self-renewing and multipotent adult stem cell populations residing in the crypt of the small intestine, capable of supporting regeneration of the intestinal epithelium (1, 2). Despite their similar ability to functionally repopulate the intestinal epithelium as demonstrated by independent in vivo lineage tracing experiments in reporter mice, the intestinal stem cells (ISCs) identified by these two molecular markers are spatially distinct. Whereas Lgr5 + ISCs are crypt base columnar (CBC) cells (1, 3) interspersed between Paneth cells and expressed throughout the intestine, Bmi1 + ISCs are mostly restricted to the "+4" cell position abutting the uppermost Paneth cell in proximal small intestine crypts (2). Lgr5 + ISCs are actively cycling (1), equipotent, and contribute to intestinal homeostasis by neutral drift competition (4-6). By comparison, Bmi1 + ISCs are less well characterized, and because of the lack of direct evidence, their cell cycle status is variably ascribed to be rapidly (7) vs. slowly cycling (8). It has been suggested that Bmi1 and Lgr5 mark an overlapping and possibly identical or redundant population of ISCs (5, 7, 9); however, no direct exploration of their functional similarities and differences has been performed. Further, it is unknown how Bmi1 + and Lgr5 + ISCs relate to a proposed model in which the intestine differentially uses an actively cycling ISC population during homeostasis and a distinct quiesce...

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“…The stem cell niche in the hair follicle bulge has different architecture. In this case, the putative niche seems to consist of a large number of stem cells grouped in a two-dimensional sheet (36). Disjoint hematopoietic stem cells have also been identified in bone marrow (37).…”

Section: Resultsmentioning

confidence: 96%

Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche

Blagoev

2011

Proc. Natl. Acad. Sci. U.S.A.

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Telomere loss at each cell replication limits the proliferative capacity of normal cells, including adult stem cells. Entering replicative senescence protects dividing cells from neoplastic transformation, but also contributes to aging of the tissue. Recent experiments have shown that intestinal mouse stem cells divide symmetrically, at random make decisions to remain stem cells or to differentiate, and gradually lose telomeric DNA. A cell's decision whether to differentiate or to remain a stem cell depends on the local cellular and chemical environment and thus tissue architecture is expected to play role in cell proliferation dynamics. To take into account the structure of the stem cell niche in determining its proliferative potential and susceptibility to cancer, a theoretical model is introduced and the niche proliferative potential is quantified for different architectures. The niche proliferative potential is quantitatively related to the proliferative potential of the individual stem cells for different structural classes of the stem cell niche. Stem cells at the periphery of a niche are under pressure to divide and to differentiate, as well as to maintain the stem cell niche boundary, and thus the geometry of the stem cell niche is expected to play a role in determining the stem cell division sequence and differentiation. Smaller surface-to-volume ratio is associated with higher susceptibility to cancer, higher tissue renewal capacity, and decreased aging rate. Several testable experimental predictions are discussed, as well the presence of stochastic effects.

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Compartmentalized organization: a common and required feature of stem cell niches?

Cited by 65 publications

References 82 publications

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development

The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations

Organ aging and susceptibility to cancer may be related to the geometry of the stem cell niche

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