scholarly journals Differential gene expression analysis identified determinants of cell fate plasticity during radiation-induced regeneration in Drosophila

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1009989
Author(s):  
Michelle Ledru ◽  
Caitlin A. Clark ◽  
Jeremy Brown ◽  
Shilpi Verghese ◽  
Sarah Ferrara ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Ribosome Biogenesis ◽  
Lineage Tracing ◽  
Therapeutic Success ◽  
Genome Wide ◽  
Radiation Induced ◽  
Differential Gene ◽  
Wing Discs ◽  
Induced Apoptosis

Ionizing radiation (IR) is used to treat half of all cancer patients because of its ability to kill cells. IR, however, can induce stem cell-like properties in non-stem cancer cells, potentiating tumor regrowth and reduced therapeutic success. We identified previously a subpopulation of cells in Drosophila larval wing discs that exhibit IR-induced stem cell-like properties. These cells reside in the future wing hinge, are resistant to IR-induced apoptosis, and are capable of translocating, changing fate, and participating in regenerating the pouch that suffers more IR-induced apoptosis. We used here a combination of lineage tracing, FACS-sorting of cells that change fate, genome-wide RNAseq, and functional testing of 42 genes, to identify two key changes that are required cell-autonomously for IR-induced hinge-to-pouch fate change: (1) repression of hinge determinants Wg (Drosophila Wnt1) and conserved zinc-finger transcription factor Zfh2 and (2) upregulation of three ribosome biogenesis factors. Additional data indicate a role for Myc, a transcriptional activator of ribosome biogenesis genes, in the process. These results provide a molecular understanding of IR-induced cell fate plasticity that may be leveraged to improve radiation therapy.

scholarly journals Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila

2018 ◽  
Author(s):  
Shilpi Verghese ◽  
Tin Tin Su
Keyword(s):  
Stem Cell ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Wing Disc ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Cancer Treatments ◽  
Therapeutic Success ◽  
Wing Discs ◽  
Regenerative Cells

ABSTRACTCancer treatments including ionizing radiation (IR) can induce cancer stem cell-like properties in non-stem cancer cells, an outcome that can interfere with therapeutic success. Yet, we understand little about what consequences of IR induces stem cell like properties and why some cancer cells show this response but not others. In previous studies, we identified a pool of epithelial cells in Drosophila larval wing discs that display IR-induced stem cell-like properties. These cells are resistant to killing by IR and, after radiation damage, change fate and translocate to regenerate parts of the disc that suffered more cell death. Here, we addressed how IR exposure results in the induction of stem cell-like behavior, and found a requirement for caspase activity. Unexpectedly, this requirement was mapped to the regenerative cells, suggesting a non-apoptotic role for caspases in the induction of stem cell-like behavior. We also performed a systematic probing of different regions of the wing disc by lineage tracing, in order to identify additional pools of cells with IR-induced regenerative properties. We identified two new populations of such cells. Unlike the original pool that helps regenerate the disc, the new pools of cells undergo abnormal regeneration to produce an ectopic, supernumerary wing disc. We also identified cells that lack the ability to display IR-induced regenerative behavior. Identification of different cell populations with different IR-induced regenerative potential will allow us to probe the molecular basis for these differences in the future.AUTHOR SUMMARYIonizing Radiation (IR), alone or in combination with other therapies, is used to treat an estimated half of all cancer patients. Yet, we understand little about why some tumors cells respond to treatment while others grow back (regenerate). We identified specific pools of cells within a Drosophila organ that are capable of regeneration after damage by IR. We also identified what it is about IR damage that allows these cells to regenerate. These results help us understand how cells regenerate after IR damage and will aid in designing better therapies that involve radiation.

Embryonic lineage tracing with Procr-CreER marks balanced hematopoietic stem cell fate during entire mouse lifespan

2019 ◽  
Vol 46 (10) ◽  
pp. 489-498 ◽  
Author(s):  
Xiaona Zheng ◽  
Guangyu Zhang ◽  
Yandong Gong ◽  
Xiaowei Ning ◽  
Zhijie Bai ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Hematopoietic Stem Cell ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Stem Cell Fate

scholarly journals Loss of p21Waf1/Cip1/Sdi1enhances intestinal stem cell survival following radiation injury

2009 ◽  
Vol 296 (2) ◽  
pp. G245-G254 ◽  
Author(s):  
Robert J. George ◽  
Mark A. Sturmoski ◽  
Randal May ◽  
Sripathi M. Sureban ◽  
Brian K. Dieckgraefe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Survival ◽  
Cell Fate ◽  
Immunohistochemical Analysis ◽  
Intestinal Stem Cell ◽  
Functional Assay ◽  
Survivin Mrna ◽  
Stem Cell Fate ◽  
Stem Cell Survival ◽  
Induced Apoptosis

The microcolony assay following gamma irradiation (IR) is a functional assay of intestinal stem cell fate. The cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1/Sdi1(p21) regulates cell cycle arrest following DNA damage. To explore the role of p21 on stem cell fate, we examined the effects of p21 deletion on intestinal crypt survival following IR and expression of the stem/progenitor cell marker Musashi-1 (Msi-1) and the antiapoptotic gene survivin. Intestinal stem cell survival in adult wild-type (WT) and p21−/−mice was measured using the microcolony assay. Msi-1, p21, and survivin mRNA were measured using real-time PCR and immunohistochemical analysis. Laser capture microdissection (LCM) was used to isolate mRNA from the crypt stem cell zone. No differences in radiation-induced apoptosis were observed between WT and p21−/−mice. However, increased crypt survival (3.0-fold) was observed in p21−/−compared with WT mice 3.5 days after 13 Gy. Msi-1 and survivin mRNA were elevated 12- and 7.5-fold, respectively, in LCM-dissected crypts of p21−/−compared with WT mice. In conclusion, deletion of p21 results in protection of crypt stem/progenitor cells from IR-induced cell death. Furthermore, the increase in crypt survival is associated with increased numbers of Msi-1- and survivin-expressing cells in regenerative crypts.

scholarly journals Recent Advances in Single-Cell View of Mesenchymal Stem Cell in Osteogenesis

2022 ◽  
Vol 9 ◽  
Author(s):  
Fangyuan Shen ◽  
Yu Shi
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Bone Development ◽  
Lineage Tracing ◽  
Research Progress ◽  
Bone Homeostasis ◽  
Differentiation Potential ◽  
Cell Technology

Osteoblasts continuously replenished by osteoblast progenitor cells form the basis of bone development, maintenance, and regeneration. Mesenchymal stem cells (MSCs) from various tissues can differentiate into the progenitor cell of osteogenic lineage and serve as the main source of osteoblasts. They also respond flexibly to regenerative and anabolic signals emitted by the surrounding microenvironment, thereby maintaining bone homeostasis and participating in bone remodeling. However, MSCs exhibit heterogeneity at multiple levels including different tissue sources and subpopulations which exhibit diversified gene expression and differentiation capacity, and surface markers used to predict cell differentiation potential remain to be further elucidated. The rapid advancement of lineage tracing methods and single-cell technology has made substantial progress in the characterization of osteogenic stem/progenitor cell populations in MSCs. Here, we reviewed the research progress of scRNA-seq technology in the identification of osteogenic markers and differentiation pathways, MSC-related new insights drawn from single-cell technology combined with experimental technology, and recent findings regarding the interaction between stem cell fate and niche in homeostasis and pathological process.

scholarly journals Metabolic Regulation of Hippocampal Neuroprogenitor Apoptosis After Irradiation

2019 ◽  
Vol 79 (3) ◽  
pp. 325-335
Author(s):  
Yu-Qing Li ◽  
Marianne Koritzinsky ◽  
C Shun Wong
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Metabolic Regulation ◽  
Neural Progenitor Cells ◽  
Adenosine Monophosphate ◽  
Adult Mice ◽  
Radiation Induced ◽  
P53 Activation ◽  
Induced Apoptosis ◽  
Metabolic Stresses

Abstract The tumor suppressor p53 is an important regulator of cell fate response after DNA damage. Cell fate response following metabolic stresses has also been linked to p53-dependent pathways. In this study, we asked if 5′-adenosine monophosphate-activated protein kinase (AMPK), the master sensor of cellular energy balance, played a role in p53-dependent apoptosis of neural progenitor cells (NPCs) in the hippocampus after irradiation. Adult mice with targeted disruption of p53 or prkaa2 (gene that encodes AMPKα) in the brain were used to determine the role of p53 and AMPK, respectively, in radiation-induced apoptosis of NPCs in the hippocampus. The p53-dependent apoptosis of NPCs was associated with an increase in phospho-AMPK expression in the dentate gyrus at 8 hours after irradiation. Activation of AMPK was seen in granule neurons and subgranular NPCs. Compared with wildtype mice, apoptosis of NPCs was significantly attenuated in AMPK deficient (nestinCre: prkaa2fl/fl) mice after irradiation. AMPK deficiency did not however alter p53 activation in NPCs after irradiation. We conclude that AMPK may regulate apoptosis of hippocampal NPCs after irradiation. These findings suggest that cellular metabolism may play a role in determining cell fate response such as apoptosis after DNA damage in NPCs.

scholarly journals aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation

2013 ◽  
Vol 202 (6) ◽  
pp. 887-900 ◽  
Author(s):  
Michaela T. Niessen ◽  
Jeanie Scott ◽  
Julia G. Zielinski ◽  
Susanne Vorhagen ◽  
Panagiota A. Sotiropoulou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Lineage Tracing ◽  
Premature Aging ◽  
Temporary Increase ◽  
Proliferative Potential ◽  
Cell Dynamics ◽  
Asymmetric Divisions

The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

scholarly journals Ribosome and Translational Control in Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 497 ◽  
Author(s):  
Mathieu Gabut ◽  
Fleur Bourdelais ◽  
Sébastien Durand
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Translational Control ◽  
Ribosome Biogenesis ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Cell Homeostasis ◽  
Cell Functions

Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.

scholarly journals Genome-Wide Interrogation of Mammalian Stem Cell Fate Determinants by Nested Chromosome Deletions

PLoS Genetics ◽  
2010 ◽  
Vol 6 (12) ◽  
pp. e1001241 ◽  
Author(s):  
Simon Fortier ◽  
Mélanie Bilodeau ◽  
Tara MacRae ◽  
Jean-Philippe Laverdure ◽  
Valeria Azcoitia ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Stem Cell Fate ◽  
Genome Wide ◽  
Chromosome Deletions ◽  
Fate Determinants ◽  
Cell Fate Determinants

PDGF-BB and bFGF ameliorate radiation-induced intestinal progenitor/stem cell apoptosis via Akt/p53 signaling in mice

2014 ◽  
Vol 307 (11) ◽  
pp. G1033-G1043 ◽  
Author(s):  
Zhihao Liu ◽  
Huiling Liu ◽  
Jie Jiang ◽  
Siwei Tan ◽  
Yidong Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Akt Inhibitor ◽  
P53 Expression ◽  
Intestinal Crypt ◽  
Akt Phosphorylation ◽  
P53 Signaling ◽  
Radiation Induced ◽  
Induced Apoptosis

Radiation-induced gastrointestinal (GI) syndrome currently has no effective prophylactic or therapeutic treatment. Previous studies and our data have demonstrated the important role of p53 in acute radiation-induced GI syndrome in mice. Many cytokines, such as tumor necrosis factor-α and fibroblast growth factor (bFGF), have been found to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. Here, we report blockage of p53 through a protein kinase B (Akt) pathway in intestinal progenitor/stem cells or crypt cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. Treatment with platelet-derived growth factor (PDGF-BB) or bFGF activated Akt phosphorylation in the intestinal crypt, lessened intestinal crypt p53 expression, decreased radiation-induced apoptosis in mouse intestinal progenitor/stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive cells by an average of 50%, and increased the survival rate of mice with abdominal radiation by 3 days in average. Conversely, the Akt inhibitor perifosine obstructed growth factor-simulated Akt phosphorylation while promoting radiation-induced p53 expression in intestinal crypts. Importantly, reduced Akt phosphorylation and elevated p53 expression due to the Akt inhibitor perifosine impaired intestinal progenitor/stem cells radioprotection provided by PDGF-BB and bFGF. Consistently, PDGF-BB and bFGF both upregulated Akt activation, suppressed radiation-induced p53 expression, and abrogated radiation-induced apoptosis in IEC-6 cells, although p53 overexpression in IEC-6 cells partially counteracted the radioprotection of PDGF-BB and bFGF. Our data suggest that intestinal crypt radioprotection by PDGF-BB and bFGF is dependent on regulation of Akt/p53 signaling.

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