Notch transactivates Rheb to maintain the multipotency of TSC-null cells

Cho, Jun-Hung; Patel, Bhaumik B.; Bonala, Santosh; Manne, Sasikanth; Zhou, Yan; Vadrevu, Surya Kumari; Patel, Jayvadan; Peronaci, Marco; Ghouse, Shanawaz M.; Henske, Elizabeth P.; Roegiers, Fabrice; Γιαννίκου, Κρινιώ; Kwiatkowski, David J.; Mansouri, Hossein; Markiewski, Maciej M.; White, Brandon; Karbowniczek, Magdalena

doi:10.1038/s41467-017-01845-1

Cited by 20 publications

(22 citation statements)

References 66 publications

(92 reference statements)

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“…This reprogramming is capable of maintaining a rapamycin non-responsive (resistant) cell population within the TSC/LAM lesions. Stemness markers have been previously identified in TSC-related cell models and involve the interplay between Notch and Rheb 69 . Interestingly, we found that expression of Dvl1 (Disheveled), an inhibitor of Notch signaling, was up-regulated in rapamycin-treated ELT3-245, compared to rapamycin-treated ELT3 cells.…”

Section: Discussionmentioning

confidence: 99%

Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Valianou

Filippidou

Johnson

et al. 2019

Sci Rep

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Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2 , leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased β-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TSC-null cells are reprogrammed to express mesenchymal-like markers. These signaling changes could be further exploited to induce clinically-relevant long-term remissions.

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Section: Discussionmentioning

confidence: 99%

Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Valianou

Filippidou

Johnson

et al. 2019

Sci Rep

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“…These observations lead to the conclusion that CD133+CD24+ renal epithelial cells may represent a multipotent stem cell population. The recent observations that amgiomyolipomas in tuberous sclerosis derive from a multipotent cancer stem cell that originate from renal epithelium confirmed the hypothesis that the renal epithelium may have differentiation capacity that goes beyond the epithelial phenotype, which was considered to be its only possible lineage based on lineage-tracing experiments performed in mouse models of AKI [96][97][98]. Consistently, CD133+CD24+ renal epithelial cells exhibit cellular plasticity and stem-like properties, such as multipotency [92,95].…”

Section: Alternative Options For Kidney Regeneration: Renal Progenitomentioning

confidence: 70%

Regenerating the kidney using human pluripotent stem cells and renal progenitors

Becherucci

Mazzinghi

Allinovi

et al. 2018

Expert Opinion on Biological Therapy

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Chronic kidney disease is a major health-care problem worldwide and its cost is becoming no longer affordable. Indeed, restoring damaged renal structures or building a new kidney represents an ambitious and ideal alternative to renal replacement therapy. Streams of research have explored the possible application of pluripotent stem cells (SCs) (embryonic SCs and induced pluripotent SCs) in different strategies aimed at regenerate functioning nephrons and at understanding the mechanisms of kidney regeneration. Areas covered: In this review, we will focus on the main potential applications of human pluripotent SCs to kidney regeneration, including those leading to rebuilding new kidneys or part of them (organoids, scaffolds, biological microdevices) as well as those aimed at understanding the pathophysiological mechanisms of renal disease and regenerative processes (modeling of kidney disease, genome editing). Moreover, we will discuss the role of endogenous renal progenitors cells in order to understand and promote kidney regeneration, as an attractive alternative to pluripotent SCs. Expert opinion: Opportunities and pitfalls of all these strategies will be underlined, finally leading to the conclusion that a deeper knowledge of the biology of pluripotent SCs is mandatory, in order to allow us to hypothesize their clinical application.

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Section: Tubular Progenitorsmentioning

confidence: 99%

“…Recently, two studies suggested that angiomyolipomas originate from multipotent kidney epithelial cells localized in the tubule and undergoing clonal expansion in response to tuberous sclerosis complex (TSC) gene deletion [ 109 , 110 ]. Both studies proposed these cells could be renal progenitors with multilineage differentiation capacity [ 109 , 110 ]. Interestingly, Cho et al revealed that the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event, was the main mechanism behind the generation of the multiple lineages present in angiomyolipoma [ 109 ].…”

Section: Tubular Progenitorsmentioning

confidence: 99%

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

Peired

Melica

Molli

et al. 2021

Cells

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Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.

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Notch transactivates Rheb to maintain the multipotency of TSC-null cells

Cited by 20 publications

References 66 publications

Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Regenerating the kidney using human pluripotent stem cells and renal progenitors

Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

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