Safety Assessment of Myogenic Stem Cell Transplantation and Resulting Tumor Formation

Jacobs, Stephanie; Lane, Felicia; Pham, Quynh Anh; Nistor, Gabriel; Robles, Rockelle; Chua, Camille; Boubion, Bryan; Osann, Kathryn; Keirstead, Hans S.

doi:10.1097/spv.0000000000000035

Cited by 11 publications

(15 citation statements)

References 21 publications

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“…Jacobs et al found no evidence of myogenic stem cell migration to the liver or lung. However, they detected local ectopic foci of growth in two treated rat anal sphincters after 30 days; the small tumors were benign tumors with no nuclear abnormalities [54]. In our study, normal histology was confirmed both by 3D mCT scanning of the whole sphincter sample area, as well as by selected histological sections.…”

Section: Discussionsupporting

confidence: 68%

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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Section: Discussionsupporting

confidence: 68%

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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“…Finally, our present results show that SC therapy on this model is safe, as no serious adverse reactions or neoplastic processes were observed. In this field, there is a worrisome paper in which 2/24 rats receiving 5 × 10 6 myogenic SCs developed local abnormal foci of growth that were benign[ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Rat model of anal sphincter injury and two approaches for stem cell administration

Trébol¹,

Georgiev-Hristov²,

Vega-Clemente³

et al. 2018

WJSC

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AIMTo establish a rat model of anal sphincter injury and test different systems to provide stem cells to injured area.METHODSAdipose-derived stem cells (ASCs) were isolated from BDIX rats and were transfected with green fluorescent protein (GFP) for cell tracking. Biosutures (sutures covered with ASCs) were prepared with 1.5 x 106 GFP-ASCs, and solutions of 106 GFP-ASCs in normal saline were prepared for injection. Anorectal normal anatomy was studied on Wistar and BDIX female rats. Then, we designed an anal sphincter injury model consisting of a 1-cm extra-mucosal miotomy beginning at the anal verge in the anterior middle line. The sphincter lesion was confirmed with conventional histology (hematoxylin and eosin) and immunofluorescence with 4', 6-diamidino-2-phenylindole (commonly known as DAPI), GFP and α-actin. Functional effect was assessed with basal anal manometry, prior to and after injury. After sphincter damage, 36 BDIX rats were randomized to three groups for: (1) Cell injection without repair; (2) biosuture repair; and (3) conventional suture repair and cell injection. Functional and safety studies were conducted on all the animals. Rats were sacrificed after 1, 4 or 7 d. Then, histological and immunofluorescence studies were performed on the surgical area.RESULTSWith the described protocol, biosutures had been covered with at least 820000-860000 ASCs, with 100% viability. Our studies demonstrated that some ASCs remained adhered after suture passage through the muscle. Morphological assessment showed that the rat anal anatomy is comparable with human anatomy; two sphincters are present, but the external sphincter is poorly developed. Anal sphincter pressure data showed spontaneous, consistent, rhythmic anal contractions, taking the form of “plateaus” with multiple twitches (peaks) in each pressure wave. These basal contractions were very heterogeneous; their frequency was 0.91-4.17 per min (mean 1.6980, SD 0.57698), their mean duration was 26.67 s and mean number of peaks was 12.53. Our morphological assessment revealed that with the aforementioned surgical procedure, both sphincters were completely sectioned. In manometry, the described activity disappeared and was replaced by a gentle oscillation of basal line, without a recognizable pattern. Surprisingly, these findings appeared irrespective of injury repair or not. ASCs survived in this potentially septic area for 7 d, at least. We were able to identify them in 84% of animals, mainly in the muscular section area or in the tissue between the muscular endings. ASCs formed a kind of “conglomerate” in rats treated with injections, while in the biosuture group, they wrapped the suture. ASCs were also able to migrate to the damaged zone. No relevant adverse events or mortality could be related to the stem cells in our study. We also did not find unexpected tissue growths.CONCLUSIONThe proposed procedure produces a consistent sphincter lesion. Biosutures and injections are suitable for cell delivery. ASCs survive and are completely safe in this clinical s...

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“…Also in 2013, Jacobs et al[ 47 ] published the first study with a safety concern. Here, 33 female virgin SpragueDawley rats received surgical anal sphincter transection and repair, after which 24 underwent the injection of 5.0 × 10 6 allogeneic MDSCs and nine served as the sham control.…”

Section: Animal Studies Publishedmentioning

confidence: 99%

“…All investigations, except two, confirm the safety and absence of relevant adverse events. There is one alert with local injection (two local benign foci of growth in nearly 400 published injected animals)[ 47 ] and another with systemic (mortality increment associated with pulmonary embolisms)[ 42 ], possibly due to the high doses employed.…”

Section: Animal Studies Publishedmentioning

confidence: 99%

Stem cell therapy for faecal incontinence: Current state and future perspectives

Trébol¹,

Carabias-Orgaz²,

García-Arranz³

et al. 2018

WJSC

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Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared (29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived (muscle derived stem cells or myoblasts derived from them) or mesenchymal (bone-marrow- or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.

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Safety Assessment of Myogenic Stem Cell Transplantation and Resulting Tumor Formation

Cited by 11 publications

References 21 publications

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

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

Rat model of anal sphincter injury and two approaches for stem cell administration

Stem cell therapy for faecal incontinence: Current state and future perspectives

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