Improvement of Anal Function by Adipose-Derived Stem Cell Sheets

Inoue, Yusuke; Fujita, Fumihiko; Yamaguchi, Izumi; Kinoe, Hiroko; Kawahara, Daisuke; Sakai, Yusuke; Kuroki, Tamotsu; Eguchi, Susumu

doi:10.1159/000475475

Cited by 13 publications

(34 citation statements)

References 19 publications

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“…This study rst developed an IAS-speci c incontinence animal model with molecular and histologic changes in SMCs in the IAS. Our incontinence model deliberately targeted SMCs in the IAS and can reduce the bias caused by involving skeletal muscle cells in previous animal models in which anal sphincterotomy was performed at both the IAS and EAS [20][21][22][23]. In the established model, implanted hADScs induced augmentation of SMCs at the injured site.…”

Section: Discussionmentioning

confidence: 99%

“…However, to investigate the functional recovery of resting pressure or SMCs in the IAS, a few animal models representing the pathophysiology of a dysfunctional IAS have been reported [20][21][22]. After applying intramuscular or intravascular injection of mesenchymal stem cells (MSCs) in an animal model, Salcedo et al [21,22] reported the functional recovery of anal resting pressure but could not detect cell differentiation or implanted MSCs at the injured site under confocal microscopy or in immuno uorescence assays.…”

Section: Discussionmentioning

confidence: 99%

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Differentiation of adipose-derived stem cells into smooth muscle cells in an internal anal sphincter-targeting faecal incontinence animal model

Kim

Lee

et al. 2022

Preprint

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Background: Studies on the development of a faecal incontinence (FI) model targeting smooth muscle cells (SMCs) of the internal anal sphincter (IAS) have not been reported. Differentiation of implanted human adipose-derived stem cells (hADScs) into corresponding SMCs in an IAS-targeting FI model has also not been demonstrated. We aimed to develop an IAS-targeting FI animal model and to determine the differentiation of hADScs into SMCs in the established IAS-targeting animal model.Methods: An IAS-targeting FI model was developed by inducing cryoinjury at the inner side of the muscular layer via posterior intersphincteric dissection in Sprague–Dawley rats. After in vitro confirmation of differentiation ability into SMCs, implantation of Dil-stained hADScs (1×106 cells per site) was immediately performed at the IAS injury site via microscopic needling. Multiple markers, including α-smooth muscle actin (α-SMA), SM22α, calponin, caldesmon, smooth muscle myosin heavy chain (SMMHC), smoothelin, stromal cell-derived factor 1 (SDF-1), monocyte chemoattractant protein 3 (MCP-3), fibronectin, CoL1A1, and transforming growth factor β (TGF-β), were used to confirm molecular changes in smooth muscles before implantation (n = 10) and after differentiation of labelled cells at one and two weeks after implantation (n = 20). These analyses were performed using H&E staining, immunofluorescence staining, Masson’s trichrome staining, and quantitative RT–PCR.Results: Impaired smooth muscle layers accompanying other intact layers were identified in the cryoinjury group. Specific SMC markers, including SM22α, calponin, caldesmon, SMMHC, smoothelin, and SDF-1 were significantly decreased in the cryoinjured group compared with levels in the control group. However, CoL1A1 was increased significantly in the cryoinjured group. In the hADSc-treated group (n = 10), higher levels of SMMHC, smoothelin, SM22α, and α-SMA were observed at two weeks after implantation than at one week after implantation. Stem cell tracking revealed that Dil-stained cells were located at the site of augmented SMCs, with a diminished population of labelled cells after implantation.Conclusions: We first established an IAS-specific FI animal model. Although we could not confirm pathologic evidence of the differentiation of implanted hADScs into SMCs at the injury site, we can infer that implanted cells could lead to augmentation of SMCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differentiation of adipose-derived stem cells into smooth muscle cells in an internal anal sphincter-targeting faecal incontinence animal model

Kim

Lee

et al. 2022

Preprint

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“…It is somewhat different from ISR for human patients with rectal cancer. Finally, combination therapy with EMS and regenerative therapy may synergistically increase the effects of each treatment (7).…”

Section: Discussion Discussionmentioning

confidence: 99%

“…Several novel therapeutic options such as bulking agents, artificial bowel sphincter etc., have been proposed, but they are not completely accepted yet. Lately, several articles have reported that mesenchymal stem cells (MSC) can improve the function of the anal sphincter after an injury in animal models, including one from our own laboratory (6,7).…”

Section: Introduction Introductionmentioning

confidence: 99%

Improvement in the Anal Function in Rats via Electrical Muscle Stimulation

Nakayama¹,

Ito²,

Fujita³

et al. 2019

SGO

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Background: Intersphincteric resection (ISR) has become a common procedure for lower rectal cancer. However, while the anus can be preserved, thereby avoiding colostomy, anal sphincter dysfunction remains a troublesome complication. This is a serious problem with no effective therapies available at present. We established a novel rat model with long-term anal sphincter dysfunction. The objective of this experiment was to assess anal functional recovery after electrical muscle stimulation (EMS) of the anal sphincter in anal dysfunction model rats. Methods: Twenty female Sprague-Dawley rats underwent resection of the approximately half of the internal and external anal sphincter. Rats were divided into two groups: one treated by electrical stimulation to anal sphincter (EMS group, n=10), and another with no treatment after surgery (control group, n=10). The EMS group rats had an electrode pad placed at the anus and received electrical stimulation. The rats were then evaluated for the anal function by measuring their resting pressure before surgery and on postoperative days. Additionally, the rats were histologically examined for the asessment of smooth muscle. Results: The pressure of the anus was not significantly different between the two groups. However, the rate of the improvement of the anal pressure was greater in the EMS group than in the control group (293.4% vs. 129.6%, p<0.005) significantly. Pathologically, the internal sphincter muscle of the bundles of the EMS group became significantly thicker (1.22 times thicker than the external ones, p<0.05). Conclusion: EMS to the anal sphincter has the therapeutic possibility to resolve anal sphincter dysfunction following anorectal surgery, including ISR.

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“…In vitro and in vivo experimental studies using bioengineered human IAS have reported that implantation of intrinsically innervated human IAS constructs generated spontaneous basal tone with myogenic and neuronal components [ 13 , 14 ]. Furthermore, FI cell treatments [ 16 - 19 ] using bone mesenchymal stem cells (MSCs), adipose stem cells (ASCs), myoblasts, and a combined treatment strategy [ 20 - 24 ] have been reported functional improvement in the injured sphincter. However, these studies for cell therapy showed a bias and lacked data for clinical use as reported by the previous systematic reviews [ 25 - 27 ].…”

Section: Introductionmentioning

confidence: 99%

A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence

Kim

Lee

et al. 2022

Ann Coloproctol

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The complexity in the molecular mechanism of the internal anal sphincter (IAS) limits preclinical or clinical outcomes of fecal incontinence (FI) treatment. So far, there are no systematic reviews of IAS translation and experimental studies that have been reported. This systematic review aims to provide a comprehensive understanding of IAS critical role in FI. Previous studies revealed the key pathway for basal tone and relaxation of IAS in different properties as follows; calcium, Rho-associated, coiled-coil containing serine/threonine kinase, aging-associated IAS dysfunction, oxidative stress, renin-angiotensin-aldosterone, cyclooxygenase, and inhibitory neurotransmitters. Previous studies have reported improved functional outcomes of cellular treatment for regeneration of dysfunctional IAS, using various stem cells, but did not demonstrate the interrelationship between those results and basal tone or relaxation-related molecular pathway of IAS. Furthermore, these results have lower specificity for IAS-incontinence due to the included external anal sphincter or nerve injury regardless of the cell type. An acellular approach using bioengineered IAS showed a physiologic response of basal tone and relaxation response similar to human IAS. However, in both cellular and acellular approaches, the lack of human IAS data still hampers clinical application. Therefore, the IAS regeneration presents more challenges and warrants more advances.

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Improvement of Anal Function by Adipose-Derived Stem Cell Sheets

Cited by 13 publications

References 19 publications

Differentiation of adipose-derived stem cells into smooth muscle cells in an internal anal sphincter-targeting faecal incontinence animal model

Differentiation of adipose-derived stem cells into smooth muscle cells in an internal anal sphincter-targeting faecal incontinence animal model

Improvement in the Anal Function in Rats via Electrical Muscle Stimulation

A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence

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