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

Abstract

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.

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

“…In addition, we consider that further translational studies are needed to determine whether SMCs newly regenerated by hADSc treatment can produce an IAS basal tone with an intrinsic force similar to that of the IAS in the host. Because our previous systematic review showed a lower interrelationship between the molecular mechanisms of IAS and functional outcomes of cell treatments due to the complexity of the molecular mechanisms for basal tone and relaxation of IAS as intrinsic properties [14].…”

“…The histologic and myogenic functions of SMCs in an IAS are different from those of skeletal muscle cells in an EAS [13]. However, the experimental study of speci c incontinence models targeting SMCs in the IAS still needs to be clari ed by reducing the bias caused by skeletal muscle cells in the EAS [14].…”

Differentiation of Adipose-Derived Stem Cells into Smooth Muscle Cells in an Internal Anal Sphincter-Targeting Anal Incontinence Rat Model

“…Moreover, cryoinjury might represent a physiological approach, similar to that in a previous study [ 26 , 27 ], as compared to a mechanical procedure, such as simple division, segmental resection or crush injury. The RhoA/ROCK (Ras homolog gene family, member A/Rho-associated, coiled-coil containing serine/threonine kinase) pathway has a critical role in determining basal tone development [ 14 ]. ROCK binds to the plasma membrane via its ‘split’ PH and C1 domains [ 28 ].…”

“…The minimum sample size was estimated for the random allocation of experimental animals to each group to develop the IAS-specific incontinence model and stem cell implantation in the established animal model according to data from our previous systematic review [ 14 ]. Statistically significant differences among groups were determined using one- or two-way analysis of variance (ANOVA), followed by Bonferroni’s post hoc test using GraphPad Prism (9.3.1) (GraphPad Software Inc., San Diego, CA, USA).…”

“…The histologic and myogenic functions of SMCs in an IAS differ from those of skeletal muscle cells in an EAS [ 13 ]. However, the experimental study of specific incontinence models targeting SMCs in the IAS requires further clarification by reducing the bias caused by skeletal muscle cells in the EAS [ 14 ].…”