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Wnt Signaling and Aging of the Gastrointestinal Tract
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This entry is adapted from the peer-reviewed paper 10.3390/ijms232012210

Wnt signaling plays an essential role in aging of the gastrointestinal tract. Aberration of Wnt signaling seen in aged animals has been shown to affect regenerative capacity and differentiation of intestinal stem cells and promote aging-related deterioration. Similarly, abnormal Wnt signaling was observed in the aged stomach. Specifically, enhanced Wnt signaling in organoids established from the stomachs of aged mice induced the expression of Tbx3, a transcription factor that suppress cellular senescence, and led to augmented cellular proliferation. The enhanced Wnt signaling was due to suppressed Dkk3, a Wnt inhibitor, in aged gastric organoids. With respect to the role of TBX3 in humans, expression of TBX3 in human gastric tissues exhibited positive correlation with patients' age whereas that of DKK3 showed negative correlation with patients' age. In addition, TBX3 expression was also confirmed in gastric cancer tissues but not in normal gastric mucosae. These findings indicated that this DKK3-Wnt-TBX3 pathway may contribute to aging-related gastric carcinogenesis.

aging stem cell stem cell aging Wnt TBX3 DKK3 stomach intestine

1. Wnt Signaling and Stem Cell Aging

One of the main causes of aging is the aging of tissue stem cells [1]. In the normal state, stem cells proliferate and differentiate to generate tissue. However, with increasing age, dysfunction of stem cells, such as decreased proliferation and/or skewing in differentiation, starts to occur, which contributes to the initiation of aging-related diseases. This age-related deterioration of stem cell function is regarded as stem-cell aging and is now considered an essential cause of aging. Intensive studies of stem cell aging have been performed on neural tissue and skeletal muscle. These studies suggest that the Wnt signaling pathway plays a pivotal role in stem cell aging.
Cho and colleagues have shown that inhibition of sFRP3, a Wnt antagonist previously reported to accumulate and suppress quiescent neural stem cells in the adult brain [2], counteracts neural stem cell aging-related neural disorders observed in genetically engineered mice which exhibit accelerated aging [3]. Similarly, Kalamakis and colleagues reported that sFRP5, another secreted Wnt antagonist, acts together with niche-derived inflammatory signals to induce quiescence of stem cells in the aged murine brain [4]. Another report from Seib and colleagues showed that the expression of Dkk1, also a Wnt antagonist, increased with age in neural progenitor cells in the murine hippocampus and led to declined cognitive function [5]. They found that neural progenitor cells of genetically engineered mice that lacked Dkk1 in the brain showed increased Wnt activity and enhanced self-renewal. In addition, mice that lacked Dkk1 in the brain did not show the age-related deterioration seen in aged Dkk1-intact mice. Taken together, these studies indicated that stem cell aging of neural progenitor cells was due to decreased Wnt signaling.
With respect to studies of stem cell aging in skeletal muscle, Brack and colleagues reported that muscle stem cells of aged mice tended to convert to fibrogenic lineages as a result of enhanced canonical Wnt signaling and that this tendency could be suppressed by Wnt inhibitors [6]. Similarly, Ahrens and colleagues reported correlation of accelerated aging with enhanced Wnt activation [7]. They showed that muscle stem cell numbers and function were impaired upon loss of Klotho expression. They also showed that stem cell function in aged stem cells could be restored by the supplementation of recombinant Klotho protein. Hence, these studies suggested that stem cell aging in muscle stem cells was due to enhanced Wnt activation.
Hair follicles are another tissue in which stem cells have been vigorously investigated. Castilho and colleagues showed that, although activation of Wnt signaling induced growth of hair follicles, prolonged exposure to the Wnt ligand led to exhaustion of stem cells and hair loss, suggesting that enhanced Wnt signaling induced stem cell aging in hair follicular stem cells [8].
These preceding studies have demonstrated that suppressed or enhanced canonical Wnt signaling regulates stem cell aging in neural, muscular, and hair tissues. Similarily it has become evident that Wnt signaling plays a pivotal role in the aging of gastrointestinal tract.

2. Wnt Signaling and Aging of the Gastrointestinal Tract

So, how does Wnt signaling affect aging of the gastrointestinal tract? A study performed by Nalapareddy and colleagues investigated the influence of aging on intestinal stem cells [9]. They showed that the regenerative response to ionizing radiation is impaired in the aged murine intestine and that this impairment was caused by reduced regenerative capacity of intestinal stem cells due to diminished Wnt signaling in aged intestinal stem cells, which exhibited reduced expression of stem cell markers. Since the absolute number of intestinal stem cells did not differ between young and aged mice, impaired regenerative capacity in aged mice was a result not of the decreased number of intestinal stem cells, but of reduced stem cell function of aged intestinal stem cells due to reduced Wnt signaling. One of the causes of diminished Wnt signaling in aged intestinal stem cells was reduced Wnt secretion from aged niche cells. The authors also showed that restoration of Wnt signaling by supplementation of Wnt3a to the culture restored the regenerative capacity of aged murine intestinal stem cells, as assessed by organoid formation. Taken together, this study of the aged murine intestine suggested that aging-related dysfunction in the intestine was caused by decreased Wnt signaling in intestinal stem cells.
Another recent study from Pentinmikko and colleagues on Wnt signaling and intestinal stem cells also reported that Wnt signaling was reduced in aged intestinal stem cells [10]. The authors showed that Wnt signaling in intestinal stem cells was diminished by production of Notum, a secreted Wnt inhibitor, by aged Paneth cells. Mechanistically, this secretion of Notum was initiated by activation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex that regulates various intracellular signals [11] and has been reported to be involved in aging [12]. Then, the activated mTORC1 inhibited peroxisome proliferator activated receptor α, which led to increased Notum expression in aged Paneth cells. Notum, secreted from aged Paneth cells, induced inhibition of Wnt signaling in Lgr5+ intestinal stem cells and led to decreased stem cell function, as measured by decreased organoid formation. Genetic deletion of Notum, as well as Wnt3a supplementation, restored the function of aged intestinal organoids, and pharmacological inhibition of Notum also restored the regenerative capacity of the aged murine intestine. Hence, this study also indicated that decreased Wnt signaling in intestinal stem cells was the underlying factor in the aging of the intestine.
On the other hand, Cui and colleagues reported the impact of augmented Wnt signaling on aged intestinal stem cells [13]. They showed that intestinal stem cells of 24-month-old mice were incapable of forming typical intestinal organoids with villus and crypt structures, such as is seen in young intestinal organoids. Instead, these cells formed big round sphere-shaped organoids devoid of differentiated cell types. However, the aged intestinal stem cells were able to form typical intestinal organoids when they were cultured in the medium with reduced R-spondin1. The authors concluded that over-responsiveness to Wnt signaling of aged intestinal stem cells mediated the aging-induced deficiency in differentiation. Their report is different from the above two reports in that these authors focused on differentiation rather than regenerative capacity, which may explain the discrepancy between the studies.
The studies above, although through a different mechanism, proposed that Wnt signaling in intestinal stem cells plays an important role in the aging of the intestinal tract. In particular, decreased Wnt signaling in aged intestinal stem cells led to impaired regenerative capacity. However, there are other reports which suggest correlation of enhanced Wnt signaling and aging of the gastrointestinal tract.
One of these studies was performed by Hayashi and colleagues, who investigated the effect of aging on the motility of the stomach. They found that the number of interstitial cells of Cajal (ICC) was decreased in the stomachs of aged mice and that this decrease was associated with impaired gastric compliance [14]. It was found that Wnt signaling was overactivated in the gastric muscles of aged mice and in the gastric corpus muscles of middle-aged humans, and that this overactivation of Wnt signaling inhibited the proliferation of ICC stem cells. Mechanistically, it was shown that TRP53 was upregulated in ICC stem cells when Wnt/β-catenin signaling was constitutively activated, which then downregulated the self-renewal genes, resulting in ICC stem cell growth arrest. Taken together, the results of this study of the aged murine stomach suggested that aging of the gastrointestinal tract was related to enhanced Wnt signaling in the stomach.
Takeuchi and colleagues reported further evidence of a correlation between enhanced Wnt signaling and aging in the stomach [15]. Gastric organoids generated from aged mice exhibited increased organoid formation and cellular proliferation compared to gastric organoids generated from young mice. These aged gastric organoids exhibited enhanced Wnt signaling. This enhancement led to the induction of T-box3 (Tbx3), a transcription factor that suppresses cellular senescence [16], in these organoids. Cellular senescence in aged gastric organoids was suppressed as a result of enhanced G2-M transition through Tbx3-induced suppression of p19ARF, p53, and p21WAF1 (Figure 1). Further analysis revealed that the enhancement in Wnt signaling was due to decreased Dkk3, a Wnt inhibitor which has been reported to be correlated with aging-related skeletal muscle atrophy [17]. Investigation of the rationale behind the suppressed Dkk3 revealed that the suppression of Dkk3 in aged gastric organoids resulted from the methylation of their Dkk3 gene.
Figure 1. Induction and evasion of cellular senescence in young and aged gastric stem cells. (a) Gastric stem cells of young mice undergo cellular senescence via G2-M arrest. (b) Dkk3 methylated aged stem cells evade cellular senescence via G2-M transition as a result of Tbx3 induction.
Taken together, the studies described above indicate that Wnt signaling plays an important role in the aging of the intestine and the stomach.
Aging is considered one of the risk factors for cancers in various organs [18]. Regarding the role of Wnt signaling in aging-related carcinogenesis, Tao and colleagues reported that enhanced Wnt signaling increased sensitivity to DNA damage in intestinal stem cells located in the base of the intestinal crypts, which can be involved in the initiation of cancers [19]. As we age, DNA mutations accumulate in stem cells and the clonal expansion of daughter cells that possess these mutations can potentially lead to cancer initiation and progression [20].
Epigenetic reprogramming in stem cells has also been reported to induce malignant neoplasm in aging stem cells [21], and methylation of tumor suppressor genes have been reported to increase with age in normal gastric mucosa [22]. Similarly, methylation of TCF4, a transcription factor that functions as the downstream effector of canonical Wnt/β-catenin signaling in normal gastric mucosa was reported to increase with age [23]. The report from Kim and colleagues also showed that knocking down TCF4 enhanced proliferation of cells in in vitro studies using a gastric cancer cell line, showing that Wnt signaling altered proliferation in aged gastric mucosa.
Regarding the epigenetic regulation, DNA methylation of the Dkk3 gene in aged gastric organoids, the cells originating from the aged gastric mucosa, led to enhanced Wnt signaling and Tbx3 induction, resulting in increased proliferation due to suppressed cellular senescence [15]. Regarding the Wnt-dependent enhanced proliferation observed in aged gastric organoids, Milavonic and colleagues reported a suggestive phenomenon [24]. They found that B-cell lymphoma cells that were once senescent and were released from senescence re-entered the cell cycle and showed Wnt-dependent enhanced clonogenic proliferation. Interestingly, this clonogenic proliferation was not observed in cells that were never senescent. It is possible that the same phenomenon is involved in clonogenic expansion of Dkk3-suppressed aged gastric organoids. Takeuchi and colleagues reported that in addition to the augmented cellular proliferation seen in the aged murine gastric organoids, analysis of human gastric tissues revealed that the expression of TBX3 in the gastric mucosa increased with the age of patients, whereas that of DKK3 showed a reciprocal trend [15]. Similarly, they also showed that TBX3 expression was increased in precancerous changes of the gastric mucosa and increased even more in gastric cancer tissues [15]. These findings suggest a possible Wnt-related molecular mechanism underlying the aging-related carcinogenesis of the stomach.

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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Naoki Asano
,
Akio Takeuchi
,
Akira Imatani
,
Masashi Saito
,
Xiaoyi Jin
,
Waku Hatta
,
Kaname Uno
,
Tomoyuki Koike
,
Atsushi Masamune
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Entry Collection: Gastrointestinal Disease
Revisions: 2 times (View History)
Update Date: 25 Oct 2022
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