Recovery of the Injured External Anal Sphincter After Injection of Local or Intravenous Mesenchymal Stem Cells

Pathi, Sujatha D.; Acevedo, Jesús F.; Keller, Patrick W.; Kishore, A. Hari; Miller, Rodney T.; Wai, Clifford Y.; Word, R. Ann

doi:10.1097/aog.0b013e3182397009

Cited by 49 publications

(65 citation statements)

References 28 publications

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“…The process of chemokine signaling has been studied by us [39]; pro-and anti-inflammatory cytokine upregulation has also been studied [35].…”

Section: Discussionmentioning

confidence: 99%

“…Adiposederived stem cells [26][27][28][29], muscle-derived stem cells [30], and mesenchymal stem cells (MSCs) [31] have been used to improve functioning of the injured myocardium and the urinary sphincter in animal models. In the anal sphincter, the effect of MSCs has been studied, although most of the studies have used ex vivo outcome testing [32][33][34][35][36][37]. In a prior preliminary study [38], we determined the effect of intramuscular and intravenous injection of bone marrow-derived MSCs on anal sphincter pressures after anal sphincter injury or pudendal nerve crush.…”

Section: Introductionmentioning

confidence: 99%

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Functional Outcome After Anal Sphincter Injury and Treatment With Mesenchymal Stem Cells

Salcedo

Penn

Damaser

et al. 2014

Stem Cells Translational Medicine

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This research demonstrates the regenerative effects of mesenchymal stem cells (MSCs) on the injured anal sphincter by comparing anal sphincter pressures following intramuscular and serial intravascular MSC infusion in a rat model of anal sphincter injury. Fifty rats were divided into injury (n = 35) and no injury (NI; n = 15) groups. Each group was further divided into i.m., serial i.v., or no-treatment (n = 5) groups and followed for 5 weeks. The injury consisted of an excision of 25% of the anal sphincter complex. Twenty-four hours after injury, 5 3 10 5 green fluorescent protein-labeled MSCs in 0.2 ml of phosphate-buffered saline (PBS) or PBS alone (sham) were injected into the anal sphincter for i.m. treatment; i.v. and sham i.v. treatments were delivered daily for 6 consecutive days via the tail vein. Anal pressures were recorded before injury and 10 days and 5 weeks after treatment. Ten days after i.m. MSC treatment, resting and peak pressures were significantly increased compared with those in sham i.m. treatment (p < .001). When compared with the NI group, the injury groups had anal pressures that were not significantly different 5 weeks after i.m./i.v. treatment. Both resting and peak pressures were also significantly increased after i.m./i.v. MSC treatment compared with treatment with PBS (p < .001), suggesting recovery. Statistical analysis was done using paired t test with Bonferroni correction. Marked decrease in fibrosis and scar tissue was seen in both MSC-treated groups. Both i.m. and i.v. MSC treatment after injury caused an increase in anal pressures sustained at 5 weeks, although fewer cells were injected i.m. The MSC-treated groups showed less scarring than the PBS-treated groups, with the i.v. infusion group showing the least scarring. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:760-767

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“…The process of chemokine signaling has been studied by us [39]; pro-and anti-inflammatory cytokine upregulation has also been studied [35].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Outcome After Anal Sphincter Injury and Treatment With Mesenchymal Stem Cells

Salcedo

Penn

Damaser

et al. 2014

Stem Cells Translational Medicine

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“…In addition, beneficial effects of direct injection of stem cells in injured anal sphincter at the time of the repair has also been explored (17). However, most of these studies were short-term and employed in vitro parameters of muscle function.…”

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confidence: 99%

Myoarchitectural and functional alterations in rabbit external anal sphincter muscle following experimental surgical trauma

Rajasekaran

Sinha

Seo

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Rajasekaran MR, Sinha S, Seo Y, Salehi M, Bhargava V, Mittal RK. Myoarchitectural and functional alterations in rabbit external anal sphincter muscle following experimental surgical trauma. Am J Physiol Gastrointest Liver Physiol 307: G445-G451, 2014. First published July 3, 2014; doi:10.1152/ajpgi.00450.2013.-Obstetrical trauma to external anal sphincter (EAS) is extremely common; however, its role in the development of anal incontinence is not clear. We examined the regenerative process and functional impact of experimental surgical trauma to EAS muscle in an animal model. Surgical myotomy, a craniocaudal incision extending along the entire length and thickness of the EAS, was performed in rabbits. Animals were allowed to recover, and anal pressures were recorded at weekly intervals for 12 wk using a custom-designed probe system to determine the length-tension property of EAS muscle. Animals were killed at predetermined time intervals, and the anal canal was harvested for histochemical studies (for determination of muscle/connective tissue/ collagen) and sarcomere length measurement. In addition, magnetic resonance diffusion tensor imaging (MR-DTI) and fiber tracking was performed to determine myoarchitectural changes in the EAS. Myotomy of the EAS muscle resulted in significant impairment of its length-tension property that showed only partial recovery during the 12-wk study period. Histology revealed marked increase in the fibrosis (connective tissue ϭ 69% following myotomy vs. 28% in controls) at 3 wk, which persisted at 12 wk. Immunostaining studies confirmed deposition of collagen in the fibrotic tissue. There was no change in the sarcomere length following myotomy. MR-DTI studies revealed disorganized muscle fiber orientation in the regenerating muscle. We conclude that, following experimental injury, the EAS muscle heals with an increase in the collagen content and loss of normal myoarchitecture, which we suspect is the cause of impaired EAS function. length-tension; fibrosis; magnetic resonance diffusion tensor imaging FECAL INCONTINENCE (FI) is extremely common and reported by 7-10% of women over 60 years of age (1, 3, 4). Childbirthrelated injury to the muscles of the anal sphincter complex is a possible cause of FI in women (11,26). The injury to these muscles occurs through several mechanisms. First is the stretch of the muscles caused by the fetus during its passage through the birth canal. Second is the trauma related to instrumentation, and third is surgical episiotomy. Women who sustain thirddegree obstetrical tear develop FI soon after delivery if muscles are not properly repaired (13). However, in the significant majority of women, injury to the anal sphincter and other pelvic floor muscle is occult. Symptoms develop in the fifth to sixth decade of life, the reasons for which are not clear.Of the three components of the anal sphincter complex [the internal anal sphincter, external anal sphincter (EAS), and puborectalis muscle (PRM)], it is generally believed that EAS muscle plays a significan...

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“…injections of MSCs after partial sphincter excision resulted in increased anal pressures 19. Pathi et al, on the other hand, did not find significant advantage in the iv‐administration of rat bone‐marrow derived MSCs compared with the PBS controls, but the local injections of MSCs were effective according to in vitro assessment 17. Recently Fitzwater et al noticed that the administration of rat myogenic stem cells enhanced the contractile function of the sphincter without significant changes in histologic morphology, which addresses the paracrine processes in stem cell therapy 14.…”

Section: Discussionmentioning

confidence: 99%

“…Previous functional anal sphincter assessments have mostly been performed in vitro using anal sphincter muscle samples from euthanized animals to measure the contractility after electrical stimulation 10, 12, 17, 37. Salcedo et al measured in vivo function of the anal sphincter after a sphincterotomy or pudendal nerve crush followed by either rat bone‐marrow derived MSC injection or saline 18.…”

Section: Discussionmentioning

confidence: 99%

Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model

Kuismanen

Juntunen

Narra

et al. 2018

Stem Cells Translational Medicine

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Anal incontinence is a devastating condition that significantly reduces the quality of life. Our aim was to evaluate the effect of human adipose stem cell (hASC) injections in a rat model for anal sphincter injury, which is the main cause of anal incontinence in humans. Furthermore, we tested if the efficacy of hASCs could be improved by combining them with polyacrylamide hydrogel carrier, Bulkamid. Human ASCs derived from a female donor were culture expanded in DMEM/F12 supplemented with human platelet lysate. Female virgin Sprague‐Dawley rats were randomized into four groups (n = 14–15/group): hASCs in saline or Bulkamid (3 × 105/60 μl) and saline or Bulkamid without cells. Anorectal manometry (ARM) was performed before anal sphincter injury, at two (n = 58) and at four weeks after (n = 33). Additionally, the anal sphincter tissue was examined by micro‐computed tomography (μCT) and the histological parameters were compared between the groups. The median resting and peak pressure during spontaneous contraction measured by ARM were significantly higher in hASC treatment groups compared with the control groups without hASCs. There was no statistical difference in functional results between the hASC‐carrier groups (saline vs. Bulkamid). No difference was detected in the sphincter muscle continuation between the groups in the histology and μCT analysis. More inflammation was discovered in the group receiving saline with hASC. The hASC injection therapy with both saline and Bulkamid is a promising nonsurgical treatment for acute anal sphincter injury. Traditional histology combined with the 3D μCT image data lends greater confidence in assessing muscle healing and continuity. Stem Cells Translational Medicine 2018;7:295–304

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Recovery of the Injured External Anal Sphincter After Injection of Local or Intravenous Mesenchymal Stem Cells

Cited by 49 publications

References 28 publications

Functional Outcome After Anal Sphincter Injury and Treatment With Mesenchymal Stem Cells

Functional Outcome After Anal Sphincter Injury and Treatment With Mesenchymal Stem Cells

Myoarchitectural and functional alterations in rabbit external anal sphincter muscle following experimental surgical trauma

Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model

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