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Frank ND, Zylberberg E, Roufai MB, Gibb SL, Miller MM. Good Manufacturing Practice-grade fibronectin for hollow-fiber bioreactor cell manufacture: a mesenchymal stromal cell case study. Cytotherapy 2025; 27:391-399. [PMID: 39718521 DOI: 10.1016/j.jcyt.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND AIMS The need for large-scale production of mesenchymal stromal cell (MSC)-based cellular therapeutics continues to grow around the globe. Manual cell expansion processes can be highly variable between operators, require significant hands-on time from skilled staff and, because of the large number of open manipulation steps required to produce cells in dose-relevant quantities, be prone to greater risk of contamination relative to automated processes. All of these can increase overall production costs and risks to the patient. In order to meet the needs of this growing industry, viable options for large-scale automation coupled with consistent and compliant ancillary materials needed to drive cell expansion are needed. METHODS In the work described herein, the automated and functionally closed hollow-fiber bioreactor system Quantum Flex (Terumo Blood and Cell Technologies, Inc., Lakewood, CO, USA) was used in conjunction with Good Manufacturing Practice (GMP)-compliant, virus-inactivated human fibronectin (FN) from Akron Bio (Boca Raton, FL, USA) to expand MSCs to clinically relevant numbers. In order to assess the performance of Akron Bio's GMP-grade FN, use of this product in the production of MSCs was referenced against use of a research-use-only (RUO)-grade FN product used extensively for MSC expansion in Quantum. Because many MSC-based processes require passaging of cells to attain the appropriate number of cells needed, a two-passage process was employed comparing the transfer of MSCs expanded on RUO FN to RUO FN, GMP FN to GMP FN and RUO FN to GMP FN to assess the impacts of transitioning from one grade of FN to another, as a product might be required to do as it moves from pre-clinical to clinical stages and beyond. RESULTS No statistically significant differences were noted when MSCs were transferred from RUO FN to RUO FN, GMP FN to GMP FN or RUO FN to GMP FN in terms of harvest yield, population doubling time, seeding efficiency estimates or fold expansion. All MSCs harvested from all groups met International Society for Cell & Gene Therapy standards for MSCs in terms of protein marker expression measured by flow cytometry, adherence to plastic, downstream cell morphology and trilineage differentiation. CONCLUSIONS The combination of Quantum Flex as an expansion platform and Akron Bio's GMP FN is seen as an attractive option for larger-scale manufacture of GMP-grade MSC products.
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Affiliation(s)
- Nathan D Frank
- Terumo Blood and Cell Technologies, Inc., Lakewood, Colorado, USA.
| | | | | | - Stuart L Gibb
- Terumo Blood and Cell Technologies, Inc., Lakewood, Colorado, USA
| | - Mindy M Miller
- Terumo Blood and Cell Technologies, Inc., Lakewood, Colorado, USA
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Laureti S, Cappelli A, Isopi C, Gentilini L, Villani R, Sorbi G, Rizzello F, Menon A, Dussias NK, Gionchetti P, Poggioli G. Autologous Microfragmented Adipose Tissue Injection in Refractory Complex Crohn's Perianal Fistulas: Long-Term Results at 6.7 Years Mean Follow-up. Inflamm Bowel Dis 2024:izae283. [PMID: 39657028 DOI: 10.1093/ibd/izae283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Nowadays, there is a clear need for new viable therapeutic options to face complex perianal Crohn's disease (PCD). Results of our previous pilot study demonstrated the efficacy and safety of local injection of autologous microfragmented adipose tissue (MFat) in this setting. This study aims to evaluate the long-term follow-up results in the same cohort of patients. METHODS Data on clinical and radiological remission and surgical recurrence rates were prospectively collected on the 15 patients with complex fistulizing PCD refractory to combined bio-surgical therapy, originally treated with local MFat injection, with a mean 6.7 years follow-up. RESULTS In our previous study, at 24-week follow-up, combined remission was reported in 66.7% of patients, while clinical remission was achieved in 93% of cases. At a 6.7-year follow-up, 9 of the 10 healed patients maintained remission. The patient with recurrence was successfully reoperated. Three out of 5 patients who failed primary combined remission were retreated, with 2 obtaining combined remission and 1 failing. One patient refused any subsequent treatment due to good quality of life. The last patient presented delayed healing at a 1-year follow-up. Overall success rate after rescue therapy at the final follow-up reached 86.6%. Safety was maintained throughout all follow-up periods. CONCLUSIONS This is the longest follow-up published trial on MFat injection for PCD. Our results show that patients who achieved closure in the first 24 weeks sustained response at long-term evaluation. In addition, there may be a rationale in repeating treatment as rescue therapy in not responding to patients.
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Affiliation(s)
- Silvio Laureti
- Department of Medical and Surgical Sciences, Surgery of the Alimentary Tract, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Alberta Cappelli
- Department of Medical and Surgical Sciences, Radiology Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Claudio Isopi
- Department of Medical and Surgical Sciences, Surgery of the Alimentary Tract, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Lorenzo Gentilini
- Department of Medical and Surgical Sciences, Surgery of the Alimentary Tract, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Riccardo Villani
- Department of Medical and Surgical Sciences, Plastic and Reconstructive Surgery Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Italy
| | - Gioia Sorbi
- Department of Medical and Surgical Sciences, Plastic and Reconstructive Surgery Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Italy
| | - Fernando Rizzello
- Department of Medical and Surgical Sciences, IBD Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Alessandra Menon
- U.O.C 1° Clinica Ortopedica, ASST Gaetano Pini-CTO, Milan, Italy
| | - Nikolas Konstantine Dussias
- Department of Medical and Surgical Sciences, IBD Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Paolo Gionchetti
- Department of Medical and Surgical Sciences, IBD Unit, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
| | - Gilberto Poggioli
- Department of Medical and Surgical Sciences, Surgery of the Alimentary Tract, IRCCS S. Orsola-Malpighi Hospital, DIMEC, University of Bologna, Bologna, Italy
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Faircloth TU, Temple S, Parr RN, Tucker AB, Rajan D, Hematti P, Kugathasan S, Chinnadurai R. Vascular endothelial growth factor secretion and immunosuppression are distinct potency mechanisms of human bone marrow mesenchymal stromal cells. Stem Cells 2024; 42:736-751. [PMID: 38826008 DOI: 10.1093/stmcls/sxae040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/23/2024] [Indexed: 06/04/2024]
Abstract
Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, the combination of inflammatory cytokines IFNγ and TNFα reduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγ mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.
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Affiliation(s)
- Tyler U Faircloth
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Sara Temple
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Rhett N Parr
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Anna B Tucker
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Devi Rajan
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
| | - Peiman Hematti
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31324, United States
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Shehab M, De Marco D, Lakatos PL, Bessissow T. The potential for medical therapies to address fistulizing Crohn's disease: a state-of-the-art review. Expert Opin Biol Ther 2024; 24:733-746. [PMID: 39045643 DOI: 10.1080/14712598.2024.2383882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/25/2024] [Accepted: 07/20/2024] [Indexed: 07/25/2024]
Abstract
INTRODUCTION Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences. AREAS COVERED This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation. EXPERT OPINION Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.
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Affiliation(s)
- Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Kuwait University, Kuwait City, Kuwait
| | - Davide De Marco
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
| | - Peter L Lakatos
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Talat Bessissow
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
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Lightner AL, Irving PM, Lord GM, Betancourt A. Stem Cells and Stem Cell-Derived Factors for the Treatment of Inflammatory Bowel Disease with a Particular Focus on Perianal Fistulizing Disease: A Minireview on Future Perspectives. BioDrugs 2024; 38:527-539. [PMID: 38914783 PMCID: PMC11247053 DOI: 10.1007/s40259-024-00661-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 06/26/2024]
Abstract
Inflammatory bowel disease remains a difficult disease to effectively treat, especially fistulizing Crohn's disease. Perianal fistulas in the setting of Crohn's disease remain an area of unmet need with significant morbidity in this patient population. Up to one third of Crohn's patients will have perianal fistulizing disease and current medical and surgical interventions are of limited efficacy. Thus, most patients experience significant morbidity, narcotic use, and loss of employment and end up with multiple surgical interventions. Mesenchymal stem cells (MSCs) have shown efficacy in phase 3 clinical trials, but considerable infrastructure challenges make MSCs limited with regard to scalability in clinical practice. Extracellular vesicles, being derived from MSCs and capturing the secretome functionality of MSCs, offer similar physiological utility regarding mechanism, while also providing an off the shelf regenerative medicine product that could be widely used in daily clinical practice.
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Affiliation(s)
- Amy L Lightner
- Surgery, Scripps Clinic, 10667 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
- Molecular Medicine, Scripps Research Institute, La Jolla, USA.
| | - Peter M Irving
- Guy's and St Thomas' Hospital, London, UK
- King's College London, London, UK
| | | | - Aline Betancourt
- Vitabolus Inc, San Diego, CA, USA
- Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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Obi M, Adams A, Vandenbossche A, Otero Pineiro A, Lightner AL. Patient engagement and satisfaction with early phase cell therapy clinical trials at a tertiary inflammatory bowel disease center. Stem Cell Reports 2024; 19:435-442. [PMID: 38552633 PMCID: PMC11096429 DOI: 10.1016/j.stemcr.2024.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 02/26/2024] [Accepted: 02/27/2024] [Indexed: 04/12/2024] Open
Abstract
Several clinical trials are underway investigating cell and gene therapy, and while these trials are meant to significantly impact patient care, they rely on patient engagement and participation. Unfortunately, clinical trials generally require extensive commitment by subjects. While several studies are using validated surveys to measure patient-reported outcomes, there is a lack of characterization of the patient experience as a subject in these trials. As such, we surveyed mesenchymal stromal cell (MSC) trial participants to understand their perspective. We found that there exists a reliance on one's gastroenterologist and colorectal surgeons for trial introduction and that time and cost were the main barriers to participation. Overall, participants demonstrated high satisfaction with MSC trial participation, but future protocols could incorporate increased use of virtual appointments to optimize patient experience.
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Affiliation(s)
- Megan Obi
- Department of General Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Ashley Adams
- Division of General Surgery, Scripps Clinic Medical Group, Scripps Health, La Jolla, CA 92037, USA
| | - Alexandria Vandenbossche
- Division of General Surgery, Scripps Clinic Medical Group, Scripps Health, La Jolla, CA 92037, USA
| | - Ana Otero Pineiro
- Department of Gastrointestinal Surgery, Hospital Clinic, Barcelona, Spain
| | - Amy L Lightner
- Division of General Surgery, Scripps Clinic Medical Group, Scripps Health, La Jolla, CA 92037, USA.
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Lightner AL, Pineiro AO, Reese J, Ream J, Nachand D, Adams AC, Dadgar N, Hull T. Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months. Surgery 2024; 175:984-990. [PMID: 38097485 DOI: 10.1016/j.surg.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/02/2023] [Accepted: 11/07/2023] [Indexed: 03/17/2024]
Abstract
BACKGROUND Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH.
| | - Ana Otero Pineiro
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Jane Reese
- National Center for Regenerative Medicine, Cleveland, OH
| | - Justin Ream
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Douglas Nachand
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Ashley C Adams
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Tracy Hull
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
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9
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Park MY, Yoon YS, Park JH, Lee JL, Yu CS. Long-term outcome of stem cell transplantation with and without anti-tumor necrotic factor therapy in perianal fistula with Crohn's disease. World J Stem Cells 2024; 16:257-266. [PMID: 38577230 PMCID: PMC10989284 DOI: 10.4252/wjsc.v16.i3.257] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/25/2023] [Accepted: 02/18/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn's disease (CD). Anti-tumor necrotic factor (TNF) therapy combined with drainage procedure is effective as well. However, previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure. AIM This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn's perianal fistula (CPF) closure rates after stem cell transplantation with and without anti-TNF therapy, and to identify the factors affecting CPF closure and recurrence. METHODS The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled. Clinical data were compared according to anti-TNF therapy and CPF closure. RESULTS A total of 65 patients were included. The median age of females was 26 years (range: 21-31) and that of males was 29 (44.6%). The mean follow-up duration was 65.88 ± 32.65 months, and complete closure was observed in 50 (76.9%) patients. The closure rates were similar after stem cell transplantation with and without anti-TNF therapy (66.7% vs 81.6% at 3 year, P = 0.098). The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture (P = 0.027, 0.002, and 0.008, respectively). Clinical factors such as complexity, number of fistulas, presence of concurrent abscess, and medication were not significant for closure. The cumulative 1-, 2-, and 3-year closure rates were 66.2%, 73.8%, and 75.4%, respectively. CONCLUSION Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation. However, both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy. Fistulous tract length, proctitis, and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.
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Affiliation(s)
- Min Young Park
- Division of Colon and Rectal Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea.
| | - Jae Ha Park
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Jong Lyul Lee
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Chang Sik Yu
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
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Lightner AL, Reese JS, Ream J, Nachand D, Dadgar N, Adams A, VanDenBossche A, Pineiro AO, Hull T. A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease. Surgery 2024; 175:242-249. [PMID: 37661485 DOI: 10.1016/j.surg.2023.07.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH.
| | - Jane S Reese
- Case Western Reserve University National Center for Regenerative Medicine, Cleveland, OH
| | - Justin Ream
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Douglas Nachand
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, OH
| | - Ashley Adams
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Alexandra VanDenBossche
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Ana Otero Pineiro
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Tracy Hull
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
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11
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CASTIGLIONI B, LEIGHEB M, BOSETTI M. Adipose derived stem cells versus micro-fragmented adipose tissue in cartilage tissue regeneration and repair. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2024; 182. [DOI: 10.23736/s0393-3660.23.05381-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
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Lightner AL, Kurowski J, Otero-Pinerio AM. Direct Injection of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Crohn's Perianal Fistulizing Disease. Dis Colon Rectum 2024; 67:e115-e116. [PMID: 37728573 DOI: 10.1097/dcr.0000000000002767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/21/2023]
Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Scripps Clinic, San Diego, California
| | - Jacob Kurowski
- Department of Pediatric Gastroenterology, Pediatric Institute, Cleveland Clinic, Cleveland Ohio
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Lightner AL, Otero-Pineiro A, Reese J, Ream J, Nachand D, Adams AC, VanDenBossche A, Kurowski JA. A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease. Inflamm Bowel Dis 2023; 29:1912-1919. [PMID: 37263018 DOI: 10.1093/ibd/izad100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ana Otero-Pineiro
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jane Reese
- National Center for Regenerative Medicine, Cleveland, OH, USA
| | - Justin Ream
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Douglas Nachand
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ashley C Adams
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Alexandra VanDenBossche
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jacob A Kurowski
- Department of Pediatrics, Pediatric Institute, Cleveland Clinic, Cleveland, OH, USA
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Wei J, Zhang Y, Chen C, Feng X, Yang Z, Feng J, Jiang Q, Fu J, Xuan J, Gao H, Liao L, Wang F. Efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells for the treatment of complex perianal fistula in Crohn's disease: a pilot study. Stem Cell Res Ther 2023; 14:311. [PMID: 37904247 PMCID: PMC10617053 DOI: 10.1186/s13287-023-03531-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 10/10/2023] [Indexed: 11/01/2023] Open
Abstract
OBJECTIVES The aim of the study was to evaluate the efficacy and safety of allogeneic umbilical cord-derived mesenchymal stem cells (TH-SC01) for complex perianal fistula in patients with Crohn's disease (CD). METHODS This was an open-label, single-arm clinical trial conducted at Jinling Hospital. Adult patients with complex treatment-refractory CD perianal fistulas (pfCD) were enrolled and received a single intralesional injection of 120 million TH-SC01 cells. Combined remission was defined as an absence of suppuration through an external orifice, complete re-epithelization, and absence of collections larger than 2 cm measured by magnetic resonance imaging (MRI) at 24 weeks after cell administration. RESULTS A total of 10 patients were enrolled. Six patients (60.0%) achieved combined remission at 24 weeks. The number of draining fistulas decreased in 9 (90.0%) and 7 (70.0%) patients at weeks 12 and 24, respectively. Significant improvement in Perianal Crohn Disease Activity Index, Pelvic MRI-Based Score, Crohn Disease Activity Index, and quality of life score were observed at 24 weeks. No serious adverse events occurred. The probability of remaining recurrence-free was 70% at week 52. CONCLUSION The study demonstrated that local injection of TH-SC01 cells might be an effective and safe treatment for complex treatment-refractory pfCD after conventional and/or biological treatments fail (ClinicalTrials.gov ID, NCT04939337). TRIAL REGISTRATION The study was retrospectively registered on www. CLINICALTRIALS gov (NCT04939337) on June 25, 2021.
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Affiliation(s)
- Juan Wei
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Yufei Zhang
- Department of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Chunyan Chen
- Department of Gastroenterology and Hepatology, The First School of Clinical Medicine, Southern Medical University, Guangzhou Da Dao Bei 1838, Guangzhou, China
| | - Xiaoyue Feng
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Zhao Yang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Jing Feng
- Department of Gastroenterology and Hepatology, The First School of Clinical Medicine, Southern Medical University, Guangzhou Da Dao Bei 1838, Guangzhou, China
| | - Qiong Jiang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Jinjin Fu
- Department of Gastroenterology and Hepatology, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou, China
| | - Ji Xuan
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Hong Gao
- Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China
| | - Lianming Liao
- Center of Laboratory Medicine, Union Hospital of Fujian Medical University, No. 29, Xinquan Road, Fuzhou, 350001, People's Republic of China.
| | - Fangyu Wang
- Department of Gastroenterology and Hepatology, Jinling Hospital, Affiliated Hospital of Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, People's Republic of China.
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Mohammadi TC, Jazi K, Bolouriyan A, Soleymanitabar A. Stem cells in treatment of crohn's disease: Recent advances and future directions. Transpl Immunol 2023; 80:101903. [PMID: 37541629 DOI: 10.1016/j.trim.2023.101903] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/11/2023] [Accepted: 07/22/2023] [Indexed: 08/06/2023]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) is an inflammatory bowel disease that can affect any part of the intestine. There is currently no recognized cure for CD because its cause is unknown. One of the modern approaches that have been suggested for the treatment of CD and other inflammatory-based disorders is cell therapy. METHODS Search terms were stem cell therapy, CD, adipose-derived stem cells, mesenchymal stem cells, and fistula. Of 302 related studies, we removed duplicate and irrelevant papers and identified the ones with proper information related to our scope of the research by reviewing all the abstracts and categorizing each study into the proper section. RESULTS AND CONCLUSION Nowadays, stem cell therapy is widely implied in treating CD. Although mesenchymal and adipose-derived tissue stem cells proved to be safe in treating Crohn's-associated fistula, there are still debates on an optimal protocol to use. Additionally, there is still a lack of evidence on the efficacy of stem cell therapy for intestinal involvement of CD. Future investigations should focus on preparing a standard protocol as well as luminal stem cell therapy in patients.
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Affiliation(s)
| | - Kimia Jazi
- Student Research Committee, Faculty of Medicine, Medical University of Qom, Qom, Iran
| | - Alireza Bolouriyan
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
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16
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Lightner AL, Reese J, Ream J, Nachand D, Jia X, Dadgar N, Steele SR, Hull T. A Phase IB/IIA Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Perianal Fistulizing Crohn's Disease. Dis Colon Rectum 2023; 66:1359-1372. [PMID: 36602511 DOI: 10.1097/dcr.0000000000002567] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Mesenchymal stem cells have been used for the treatment of perianal Crohn's fistulizing disease by direct injection. However, no studies to date have included patients with proctitis, anal canal involvement, and multiple branching tracts. OBJECTIVE This study aimed to determine safety and efficacy of mesenchymal stem cells for refractory perianal Crohn's disease. DESIGN Phase IB/IIA randomized controlled trial. SETTINGS Tertiary IBD referral center. PATIENTS Adult Crohn's disease patients with perianal fistulizing disease. INTERVENTION Seventy-five million mesenchymal stem cells were administered with a 22-G needle by direct injection after curettage and primary closure of the fistula tract. A repeat injection of 75 million mesenchymal stem cells at 3 months was given if complete clinical and radiographic healing were not achieved. MAIN OUTCOMES MEASURES Adverse and serious adverse events occurred at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per MRI, and patient-reported outcomes were collected at the same time points. RESULTS A total of 23 patients were enrolled and treated; 18 were treatment patients and 5 were control. There were no adverse or serious adverse events reported related to mesenchymal stem cell therapy. At 6 months, 83% of the treatment group and 40% of the control group had complete clinical and radiographic healing. The perianal Crohn's disease activity index, Wexner incontinence score, and VanAssche score had all significantly decreased in treatment patients at 6 months; none significantly decreased in the control group. LIMITATIONS Single institution and single blinded. CONCLUSIONS Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C128 . UN ESTUDIO DE FASE IB/IIA DE CLULAS MADRE MESENQUIMALES DERIVADAS DE MDULA SEA ALOGNICA EXPANDIDA EX VIVO PARA EL TRATAMIENTO DE LA ENFERMEDAD DE CROHN FISTULIZANTE PERIANAL ANTECEDENTES:Las células madre mesenquimales se han utilizado para el tratamiento de la enfermedad fistulizante de Crohn perianal mediante inyección dirigida. Sin embargo, ningún estudio hasta la fecha ha incluido pacientes con proctitis, afectación del canal anal y vías de ramificación múltiples.OBJETIVO:Determinar la seguridad y eficacia de las células madre mesenquimales para la enfermedad de Crohn perianal refractaria.DISEÑO:Ensayo de control aleatorizado de fase IB/IIA.AJUSTES:Centro de referencia de enfermedad inflamatoria intestinal terciaria.PACIENTES:Pacientes adultos con enfermedad de Crohn con enfermedad fistulizante perianal.INTERVENCIÓN:Se administraron 75 millones de células madre mesenquimales con una aguja 22G mediante inyección directa después del legrado y cierre primario del trayecto de la fístula. Se administró una inyección repetida de 75 millones de células madre mesenquimales a los 3 meses si no se lograba una curación clínica y radiográfica completa.PRINCIPALES MEDIDAS DE RESULTADOS:eventos adversos y adversos graves en el día 1, la semana 2, la semana 6, el mes 3, el mes 6 y el mes 12 después del procedimiento. Curación clínica, curación radiográfica por imagen de resonancia magnética y resultados informados por el paciente en los mismos puntos de tiempo.RESULTADOS:Un total de 23 pacientes fueron reclutados y tratados; 18 fueron de tratamiento y 5 de control. No se informaron eventos adversos o adversos graves relacionados con la terapia con células madre mesenquimales. A los seis meses, el 83 % del grupo de tratamiento y el 40 % del control tenían una curación clínica y radiográfica completa. El índice de actividad de la enfermedad de Crohn perianal, la puntuación de incontinencia de Wexner y la puntuación de VanAssche habían disminuido significativamente en los pacientes de tratamiento a los seis meses; ninguno disminuyó significativamente en el grupo de control.LIMITACIONES:Institución única y simple ciego.CONCLUSIONES:Las células madre mesenquimales derivadas de la médula ósea ofrecen un d tratamiento alternativo seguro y eficaz para la enfermedad de Crohn fistulizante perianal grave. Consulte Video Resumen en http://links.lww.com/DCR/C128 . (Traducción-Dr Yolanda Colorado ).
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jane Reese
- National Center for Regenerative Medicine, Cleveland, Ohio
| | - Justin Ream
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
| | - Douglas Nachand
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
| | - Xue Jia
- Department of General Surgery, Statistics, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
| | - Neda Dadgar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Scott R Steele
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
| | - Tracy Hull
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio
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Zhang MM, Hu Y, Xu J, Liu L, Lv LL. The Impact of Cellular Therapies on Gastrointestinal Diseases: Applications and Challenges. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2023; 34:782-794. [PMID: 37485563 PMCID: PMC10544052 DOI: 10.5152/tjg.2023.23137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/09/2023] [Indexed: 07/25/2023]
Abstract
Gastrointestinal diseases are highly prevalent, and their burden significantly impacts the quality of life of affected individuals. Inflammatory and immune-mediated intestinal diseases usually have a chronic course without adequate therapeutic modalities. Although much has been reported to comprehend these diseases, many remain resistant and refractory to conventional treatment approaches. Therefore, recent approaches to cellular therapy using stem cells, like hematopoietic stem cells and mesenchymal stem cells, and other cellular immunosuppressive modalities, like T-regulatory cells, were introduced and investigated in treating gastrointestinal diseases. We aimed to conduct a literature review to discuss the applications and challenges of cellular therapeutics in gastrointestinal diseases. Evidence from published clinical trials supports the safety and efficacy of cellular treatment in different immune-mediated and inflammatory gastrointestinal diseases. They can offer a longer duration of remission, being able to adjust the dysregulated immune system. However, there are various challenges to be considered by future trials, including the limitations of current clinical trials, challenges in retrieval and application of these therapeutics, and their mutagenesis potential.
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Affiliation(s)
- Meng-Meng Zhang
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University Faculty of Medicine, Hangzhou, Zhejiang Province, China
| | - Yan Hu
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University Faculty of Medicine, Hangzhou, Zhejiang Province, China
| | - Jing Xu
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University Faculty of Medicine, Hangzhou, Zhejiang Province, China
| | - Ling Liu
- Department of Gastroenterology, Hangzhou Shangcheng District People’s Hospital, Hangzhou, Zhejiang Province, China
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University Faculty of Medicine, Hangzhou, Zhejiang Province, China
| | - Lu-Lu Lv
- Department of Gastroenterology, Shengzhou People’s Hospital (the First Affiliated Hospital of Zhejiang University Shengzhou Branch), Zhejiang University, Shengzhou, Zhejiang Province, China
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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Lightner AL, Dadgar N, Vaidya A, Simon R, Fulmer C, Siddiki H, Narayanan Menon KV, Liu P, Matthew Walsh R. Mesenchymal stem cells: A novel treatment option for primary sclerosing cholangitis. Cell Biol Int 2023; 47:467-479. [PMID: 36321586 DOI: 10.1002/cbin.11943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 10/06/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive liver disease for which there is no effective therapy. Hepatocytes and cholangiocytes from a PSC patient were cocultured with mesenchymal stem cells (MSCs) to assess in vitro change. A single patient with progressive PSC was treated with 150 million MSCs via direct injection into the common bile duct. Coculture of MSCs with cholangiocytes and hepatocytes showed in vitro improvement. Local delivery of MSCs into a single patient with progressive PSC was safe. Radiographic and endoscopic evaluation showed stable distribution of multifocal structuring in the early postoperative period. MSCs may be effective for the treatment of PSC.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anil Vaidya
- Department of Abdominal Transplantation, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Robert Simon
- Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Clifton Fulmer
- Department of Pathology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Hassan Siddiki
- Department of Gastroenterology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - K V Narayanan Menon
- Department of Gastroenterology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Peter Liu
- Department of Radiology, Imaging Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - R Matthew Walsh
- Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Dozois EJ, Lightner AL, Dietz AB, Fletcher JG, Lee YS, Friton JJ, Faubion WA. Durable Response in Patients With Refractory Fistulizing Perianal Crohn's Disease Using Autologous Mesenchymal Stem Cells on a Dissolvable Matrix: Results from the Phase I Stem Cell on Matrix Plug Trial. Dis Colon Rectum 2023; 66:243-252. [PMID: 36538706 DOI: 10.1097/dcr.0000000000002579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Refractory perianal Crohn's disease remains notoriously difficult to treat. We developed a novel technology using a commercially available bioabsorbable fistula plug to deliver autologous adipose-derived mesenchymal stem cells. OBJECTIVE This study aimed to assess therapeutic safety and feasibility in the completed STOMP (stem cells on matrix plugs) phase 1 clinical trial. DESIGN Prospective single-arm phase I clinical trial. SETTING Tertiary academic medical center. PATIENTS Adults (aged 18-65 y) with complex single-tract Crohn's disease perianal fistula who have failed conventional therapy were included in this study. INTERVENTION Autologous adipose-derived mesenchymal stem cells were isolated, ex vivo culture expanded, and seeded onto a commercially available bioabsorbable fistula plug. Six weeks later, patients returned to the operating room for removal of the seton and placement of the stem cell-loaded plug. MAIN OUTCOME MEASURES Patients were followed up for a total of 8 visits through 12 months. Safety was the primary end point; clinical healing and MRI response were secondary end points. RESULTS Twenty patients (12 females; mean age 36 y) were treated with the stem cell-loaded plug. Of the 20 patients enrolled, 3 were not included in the 12-month analysis because of study withdrawal. Through 12 months, no patient experienced a serious adverse event related to the stem cell-loaded plug. Four patients experienced 7 serious adverse events and 12 patients experienced 22 adverse events. Complete clinical healing occurred in 14 of 18 patients at 6 months and 13 of 17 patients at 12 months. MRI response was observed in 12 of 18 patients at 6 months. LIMITATIONS The main limitations were the small sample size and restrictive inclusion criteria. CONCLUSIONS A stem cell-loaded plug can safely and effectively deliver cell-based therapy for patients with single-tract fistulizing perianal Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C70 . RESPUESTA DURADERA OBSERVADA EN PACIENTES CON ENFERMEDAD DE CROHN PERIANAL FISTULIZANTE REFRACTARIA MEDIANTE EL USO DE CLULAS MADRE MESENQUIMALES AUTLOGAS EN UNA MATRIZ DISOLUBLE RESULTADOS DEL ENSAYO DE FASE I STEM CELL ON MATRIX PLUG ANTECEDENTES:La enfermedad de Crohn perianal refractaria sigue siendo notoriamente difícil de tratar. Desarrollamos una tecnología novedosa utilizando un tapón de fístula bioabsorbible disponible comercialmente para administrar células madre mesenquimales derivadas de tejido adiposo autólogo.OBJETIVO:Evaluar la seguridad y viabilidad terapéutica en el ensayo finalizado STOMP.DISEÑO:Ensayo clínico prospectivo de fase I de un solo brazo.AJUSTE:Centro médico académico terciario.PACIENTES:Adultos (18-65) con fístula perianal compleja de la enfermedad de Crohn de un solo tracto que han fracasado con la terapia convencional.INTERVENCIÓN:Se aislaron células madre mesenquimales derivadas de tejido adiposo autólogo, se expandieron en cultivo ex vivo y se sembraron en un tapón de fístula bioabsorbible disponible comercialmente. Seis semanas después, los pacientes regresaron al quirófano para retirar el setón y colocar el tapón cargado de células madre.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron seguidos durante un total de 8 visitas durante 12 meses. La seguridad fue el criterio principal de valoración; la curación clínica y la respuesta a la resonancia magnética fueron criterios de valoración secundarios.RESULTADOS:Veinte pacientes (12 mujeres, edad media 36 años) fueron tratados con el tapón cargado de células madre. De los 20 pacientes inscritos, tres no se incluyeron en el análisis de 12 meses porque se retiraron del estudio. A lo largo de 12 meses, ningún paciente experimentó un evento adverso grave relacionado con el tapón cargado de células madre. Cuatro pacientes experimentaron 7 eventos adversos graves y 12 pacientes experimentaron 22 eventos adversos. La curación clínica completa ocurrió en 14 de 18 pacientes a los 6 meses y en 13 de 17 pacientes a los 12 meses. La respuesta a la resonancia magnética se observó en 12 de 18 pacientes a los 6 meses.LIMITACIONES:Las principales limitaciones son el tamaño pequeño de la muestra y los criterios de inclusión restrictivos.CONCLUSIONES:Un tapón cargado de células madre se puede administrar de manera segura y efectiva, una terapia basada en células para pacientes con enfermedad de Crohn perianal fistulizante de un solo tracto. Consule Video Resumen en http://links.lww.com/DCR/C70 . (Traducción- Dr. Yesenia Rojas-Khalil ).
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Affiliation(s)
- Eric J Dozois
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota
| | - Amy L Lightner
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota
| | - Allan B Dietz
- Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota
| | | | - Yong S Lee
- Department of Radiology, Mayo Clinic, Rochester, Minnesota
| | - Jessica J Friton
- Department of Gastroenterology, Mayo Clinic, Rochester Minnesota
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21
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran.,Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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22
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Lightner AL, Reese J, Ream J, Nachand D, Jia X, Pineiro AO, Dadgar N, Steele S, Hull T. A Phase IB/IIA study of allogeneic bone marrow derived mesenchymal stem cells for the treatment of refractory ileal anal anastomosis and peripouch fistulas in the setting of Crohn's disease of the pouch. J Crohns Colitis 2022; 17:480-488. [PMID: 36322714 DOI: 10.1093/ecco-jcc/jjac172] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND AIMS Mesenchymal stem cells (MSCs) have been used for the treatment of perianal Crohn's fistulizing disease by direction injection. No studies to date have included patients with an ileal pouch anal anastomosis (IPAA) in situ. METHODS A phase IB/IIA randomized control trial of bone marrow derived allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula(s) was conducted. 75 million MSCs were administered with a 22G needle; repeat injection at 3 months was given if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at post procedure day 1, week 2, week 6, month 3, month 6 and month 12 were assessed. Clinical healing, radiographic healing per pelvic MRI, and patient reported outcomes were assessed at the same time points. RESULTS A total of 22 patients were enrolled and treated; 16 were treatment and 6 were control. There were no adverse or serious adverse events related to MSC therapy. At six months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal (n=7) and anovaginal (n=8) fistulas, 6 month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index (PCDAI), Wexner incontinence score, and VanAssche score all significantly decreased in treatment patients at six months; only the PCDAI decreased in the control group. CONCLUSION Bone marrow derived allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
| | - Jane Reese
- National Center for Regenerative Medicine, Cleveland, OH
| | - Justin Ream
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
| | - Douglas Nachand
- Department of Abdominal Radiology, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
| | - Xue Jia
- Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland OH
| | - Ana Otero Pineiro
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
| | - Neda Dadgar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland OH
| | - Scott Steele
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
| | - Tracy Hull
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland OH
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23
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Lightner AL, Dadgar N, Matyas C, Elliott K, Fulmer C, Khaitan N, Ream J, Nachand D, Steele SR. A phase IB/IIA study of remestemcel-L, an allogeneic bone marrow-derived mesenchymal stem cell product, for the treatment of medically refractory ulcerative colitis: an interim analysis. Colorectal Dis 2022; 24:1358-1370. [PMID: 35767384 PMCID: PMC9795998 DOI: 10.1111/codi.16239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 05/27/2022] [Accepted: 06/24/2022] [Indexed: 12/30/2022]
Abstract
AIM There have been no studies into the direct injection of mesenchymal stem cells (MSCs) for luminal ulcerative colitis (UC). Our aim was to investigate the efficacy of MSCs delivered locally via endoscopic delivery, as is done in the setting of perianal disease, to treat the local site of inflammation directly. METHOD A phase IB/IIA randomized control clinical trial of remestemcel-L, an ex vivo expanded allogeneic bone marrow-derived MSC product, at a dose of 150 million MSCs versus placebo (2:1 fashion) delivered via direct injection using a 23-gauge sclerotherapy needle at the time of colonoscopy was designed to assess the safety and efficacy of endoscopic delivery of MSCs for UC. The main outcome measures were adverse events, Mayo score and Mayo endoscopic severity score at 2 weeks, 6 weeks and 3 months post-MSC delivery. RESULTS Six patients were enrolled and treated; four received MSCs and two placebo. All had been on prior anti-tumour necrosis factor or anti-integrin therapy. There were no adverse events related to MSCs. In the treatment group (n = 4), the Mayo endoscopic severity score decreased in all patients by 2 weeks after MSC delivery. At 3 months, all patients were extremely satisfied or satisfied with their MSC treatment based on the inflammatory bowel disease patient-reported treatment impact (IBD-PRTI), and treatment response was described as excellent or good in all patients. In the control group (n = 2), the Mayo endoscopic severity score did not increase as a result of being off alternative therapy. At 3 months, patients were dissatisfied according to the IBD-PRTI, and treatment response was poor or unchanged. CONCLUSION MSCs may offer a safe therapeutic option for the treatment of medically refractory UC. Early data suggest improved clinical and endoscopic scores by 2 weeks after MSC delivery.
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Affiliation(s)
- Amy L. Lightner
- Department of Colorectal SurgeryDigestive Disease and Surgery Institute, Cleveland ClinicClevelandOhioUSA,Department of Inflammation and ImmunityLerner Research Institute, Cleveland ClinicClevelandOhioUSA
| | - Neda Dadgar
- Department of Inflammation and ImmunityLerner Research Institute, Cleveland ClinicClevelandOhioUSA
| | - Caroline Matyas
- Department of Colorectal SurgeryDigestive Disease and Surgery Institute, Cleveland ClinicClevelandOhioUSA
| | - Kavita Elliott
- Department of Colorectal SurgeryDigestive Disease and Surgery Institute, Cleveland ClinicClevelandOhioUSA
| | - Clifton Fulmer
- Department of PathologyRobert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland ClinicClevelandOhioUSA
| | - Neha Khaitan
- Department of PathologyRobert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland ClinicClevelandOhioUSA
| | - Justin Ream
- Department of RadiologyImaging Institute, Cleveland ClinicClevelandOhioUSA
| | - Douglas Nachand
- Department of RadiologyImaging Institute, Cleveland ClinicClevelandOhioUSA
| | - Scott R. Steele
- Department of Colorectal SurgeryDigestive Disease and Surgery Institute, Cleveland ClinicClevelandOhioUSA
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24
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Ye Y, Zhang X, Su D, Ren Y, Cheng F, Yao Y, Shi G, Ji Y, Chen S, Shi P, Dai L, Su X, Deng H. Therapeutic efficacy of human adipose mesenchymal stem cells in Crohn's colon fibrosis is improved by IFN-γ and kynurenic acid priming through indoleamine 2,3-dioxygenase-1 signaling. Stem Cell Res Ther 2022; 13:465. [PMID: 36076306 PMCID: PMC9461110 DOI: 10.1186/s13287-022-03157-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/17/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic relapsing-remitting inflammatory diseases of the gastrointestinal tract that are typically categorized into two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). Although MSCs therapy has achieved encouraging outcomes in IBD therapy, objective responses are limited in colon fibrosis stenosis owing to the complicated microenvironment of CD and MSCs heterogeneity of quality. Here, we chose IFN-γ and kynurenic acid (KYNA) to overcome the low response and heterogeneity of human adipose-derived MSCs (hADSCs) to treat IBD and expand the therapeutic effects based on the excellent ability of IFN-γ and KYNA to promote indoleamine 2,3-dioxygenase-1 (IDO-1) signaling, providing a potential protocol to treat IBD and fibrosis disease. METHODS hADSCs were isolated, cultured, and identified from human abdominal adipose tissue. The CD pathology-like acute colitis and chronic colon fibrosis rat model was induced by 2,4,6-trinitrobenzen sulfonic acid (TNBS). hADSCs were pretreated in vitro with IFN-γ and KYNA and then were transplanted intravenously at day 1 and 3 of TNBS administration in colitis along with at day 1, 15, and 29 of TNBS administration in chronic colonic fibrosis. Therapeutic efficacy was evaluated by body weights, disease activity index, pathological staining, real-time PCR, Western blot, and flow cytometry. For knockout of IDO-1, hADSCs were transfected with IDO-1-targeting small gRNA carried on a CRISPR-Cas9-lentivirus vector. RESULTS hADSCs treated with IFN-γ and KYNA significantly upregulated the expression and secretion of IDO-1, which has effectively ameliorated CD pathology-like colitis injury and fibrosis. Notably, the ability of hADSCs with IDO-1 knockout to treat colitis was significantly impaired and diminished the protective effects of the primed hADSCs with IFN-γ and KYNA. CONCLUSION Inflammatory cytokines IFN-γ- and KYNA-treated hADSCs more effectively alleviate TNBS-induced colitis and colonic fibrosis through an IDO-1-dependent manner. Primed hADSCs are a promising new strategy to improve the therapeutic efficacy of MSCs and worth further research.
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Affiliation(s)
- Yixin Ye
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xiaomei Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Dongsheng Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yushuang Ren
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Fuyi Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yunqi Yao
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yanhong Ji
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Shuang Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Pengyi Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Ke-yuan Road 4, No. 1, Gao-peng Street, Chengdu, 610041, Sichuan, People's Republic of China.
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25
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Che Z, Ye Z, Zhang X, Lin B, Yang W, Liang Y, Zeng J. Mesenchymal stem/stromal cells in the pathogenesis and regenerative therapy of inflammatory bowel diseases. Front Immunol 2022; 13:952071. [PMID: 35990688 PMCID: PMC9386516 DOI: 10.3389/fimmu.2022.952071] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/12/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) represent a group of chronic inflammatory disorders of the gastrointestinal (GI) tract including ulcerative colitis (UC), Crohn’s disease (CD), and unclassified IBDs. The pathogenesis of IBDs is related to genetic susceptibility, environmental factors, and dysbiosis that can lead to the dysfunction of immune responses and dysregulated homeostasis of local mucosal tissues characterized by severe inflammatory responses and tissue damage in GI tract. To date, extensive studies have indicated that IBDs cannot be completely cured and easy to relapse, thus prompting researchers to find novel and more effective therapeutics for this disease. Due to their potent multipotent differentiation and immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) not only play an important role in regulating immune and tissue homeostasis but also display potent therapeutic effects on various inflammatory diseases, including IBDs, in both preclinical and clinical studies. In this review, we present a comprehensive overview on the pathological mechanisms, the currently available therapeutics, particularly, the potential application of MSCs-based regenerative therapy for IBDs.
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Affiliation(s)
- Zhengping Che
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Ziyu Ye
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xueying Zhang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Bihua Lin
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
| | - Weiqing Yang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yanfang Liang
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Department of Pathology, Dongguan Hospital Affiliated to Jinan University, Binhaiwan Central Hospital of Dongguan, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
| | - Jincheng Zeng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Key Laboratory of Medical Bioactive Molecular Research for Department of Education of Guangdong Province, School of Basic Medicine, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Guangdong Medical University, Zhanjiang, China
- Dongguan Metabolite Analysis Engineering Technology Center of Cells for Medical Use, Guangdong Xinghai Institute of Cell, Dongguan, China
- *Correspondence: Jincheng Zeng, ; Yanfang Liang,
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26
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Gaertner WB, Burgess PL, Davids JS, Lightner AL, Shogan BD, Sun MY, Steele SR, Paquette IM, Feingold DL. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum 2022; 65:964-985. [PMID: 35732009 DOI: 10.1097/dcr.0000000000002473] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Wolfgang B Gaertner
- Division of Colon and Rectal Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Pamela L Burgess
- Department of Surgery, Uniformed Services University of the Health Sciences, Eisenhower Army Medical Center, Fort Gordon, Georgia
| | - Jennifer S Davids
- Department of Surgery, University of Massachusetts, Worcester, Massachusetts
| | - Amy L Lightner
- Department of Colon and Rectal Surgery, Cleveland Clinic, Cleveland, Ohio
| | | | - Mark Y Sun
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Scott R Steele
- Department of Colon and Rectal Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Ian M Paquette
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Daniel L Feingold
- Division of Colorectal Surgery, Rutgers University, New Brunswick, New Jersey
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27
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Wei LN, Wu CH, Lin CT, Liu IH. Topical applications of allogeneic adipose-derived mesenchymal stem cells ameliorate the canine keratoconjunctivitis sicca. BMC Vet Res 2022; 18:217. [PMID: 35689226 PMCID: PMC9185903 DOI: 10.1186/s12917-022-03303-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 05/18/2022] [Indexed: 11/10/2022] Open
Abstract
Background Canine keratoconjunctivitis sicca (KCS) is predominantly an immune-mediated disease. Current therapy of canine KCS is mainly by immunosuppressant, but the effectiveness was limited in some patients. In the past few years, some studies showed the results of the use of mesenchymal stem cells in treating canine KCS via periocular injections. However, the periocular injection procedure requires sedation or general anesthesia, and may lead to iatrogenic or incidental injury during the injection process. The aim of this study was to investigate the efficacy of topical allogenic canine adipose-derived mesenchymal stem cells (cAD-MSCs) in clinical patients of canine KCS. Results The cAD-MSCs used in this study were characterized for their capability of tri-lineage differentiation and immunomodulatory properties. In addition, preparation methods for eye drops of cAD-MSCs was developed and its optimal preservation was tested. The canine KCS patients were recruited for clinical trial and divided into two groups based on their history of previous treatment. All patients received topical cAD-MSCs treatment once per week for 6 consecutive weeks and complete ophthalmic examinations were performed 1 week before treatment (week 0) and at 3rd, 6th, 9th weeks, respectively. The results showed that the quantity and quality of tears have improved significantly following topical cAD-MSCs treatment based on Schirmers tear test-1 and tear break-up time. More than half of all patients were found improved in the tear quantity. In particular, 56.5% of the patients that were unresponsive to prior immunosuppressant therapy had an effective increase in tear volume. The severity of clinical signs was also ameliorated according to the numeric rating scale score from both patient owners and the clinician. Conclusion To sum up, topical cAD-MSCs may be beneficial especially in KCS patients with poor owner compliance for frequent daily use of eye drops or those who are unresponsive to immunosuppressant therapy.
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Affiliation(s)
- Li-Ning Wei
- Institute of Veterinary Clinical Sciences, School of Veterinary Medicine, National Taiwan University, Taipei, 106, Taiwan.,Department of Ophthalmology, National Taiwan University Veterinary Hospital, Taipei, 106, Taiwan
| | - Ching-Ho Wu
- Institute of Veterinary Clinical Sciences, School of Veterinary Medicine, National Taiwan University, Taipei, 106, Taiwan.,Department of Small Animal Surgery, National Taiwan University Veterinary Hospital, Taipei, 106, Taiwan
| | - Chung-Tien Lin
- Institute of Veterinary Clinical Sciences, School of Veterinary Medicine, National Taiwan University, Taipei, 106, Taiwan. .,Department of Ophthalmology, National Taiwan University Veterinary Hospital, Taipei, 106, Taiwan.
| | - I-Hsuan Liu
- Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan. .,Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, 106, Taiwan.
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Trophic and immunomodulatory effects of adipose tissue derived stem cells in a preclinical murine model of endometriosis. Sci Rep 2022; 12:8031. [PMID: 35577867 PMCID: PMC9110373 DOI: 10.1038/s41598-022-11891-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 04/25/2022] [Indexed: 11/24/2022] Open
Abstract
Endometriosis, which exhibits enigmatic pathological features such as stromal fibrosis and proliferation of ectopic epithelial cells, is known as a refractory disease. Mesenchymal stem cells modulate the fibrosis in stromal tissues through their trophic and immunomodulatory properties. To investigate the potential of stem cells in treating endometriosis, we examined the secondary morphology and molecular alterations in endometriosis-like lesions after the administration of adipose tissue-derived stem cells (ASCs) to an experimental murine model of endometriosis. The infused ASCs were found integrated in the endometriosis-like lesions. Accompanied by the suppression of stromal fibrosis and proliferation of endometriotic epithelial cells, the infusion of ASCs with stemness potential (early passage of ASCs) suppressed the growth of endometriosis-like lesions and inhibited the expression of pro-inflammatory and pro-fibrotic cytokines, whereas no significant attenuation of endometriosis-like lesions occurred after the infusion of ASCs without stemness potential (late passage of ASCs). Accordingly, the trophic and immunomodulatory properties of ASCs may regulate fibrosis in endometriosis-like lesions, suggesting that regenerative medicine could be recognized as an innovative treatment for patients with endometriosis through the accumulation of evidence of preclinical efficacy.
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Altemus J, Dadgar N, Li Y, Lightner AL. Adipose tissue-derived mesenchymal stem cells' acellular product extracellular vesicles as a potential therapy for Crohn's disease. J Cell Physiol 2022; 237:3001-3011. [PMID: 35522572 PMCID: PMC9544647 DOI: 10.1002/jcp.30756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/12/2022] [Accepted: 04/19/2022] [Indexed: 12/17/2022]
Abstract
The breakdown of gastrointestinal tract immune homeostasis leads to Crohn's disease (CD). Mesenchymal stem cells (MSCs) have demonstrated clinical efficacy in treating CD in clinical trials, but there is little known about the mechanism of healing. Considering the critical roles of macrophage polarization in CD and immunomodulatory properties of MSCs, we sought to decipher the interaction between adipose‐derived MSCs and macrophages, including their cytokine production, regulation of differentiation, and pro‐/anti‐inflammatory function. RNA extraction and next generation sequencing was performed in adipose tissue from healthy control patients' mesentery (n = 3) and CD mesentery (n = 3). Infiltrated macrophage activation in the CD mesentery was tested, MSCs and extracellular vesicles (EVs) were isolated to compare the regulation of macrophage differentiation, cytokines production, and self‐renewal capacities in vitro. CD patients' mesentery has increased M1 macrophage polarization and elevated activation. MSCs and their derived EVs, isolated from inflamed Crohn's mesentery, leads to a rapid differentiation of monocytes to a M1‐like polarized phenotype. Conversely, MSCs and their derived EVs from healthy, non‐Crohn's patients results in monocyte polarization into a M2 phenotype; this is seen regardless of the adipose source of MSCs (subcutaneous fat, omentum, normal mesentery). EVs derived from MSCs have the ability to regulate macrophage differentiation. Healthy MSCs and their associated EVs have the ability to drive monocytes to a M2 subset, effectively reversing an inflammatory phenotype. This mechanism supports why MSCs may be an effective therapeutic in CD and highlights EVs as a novel therapeutic for further exploration.
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Affiliation(s)
- Jessica Altemus
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Neda Dadgar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Yan Li
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Rakowsky S, Papamichael K, Cheifetz AS. Choosing the right biologic for complications of inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2022; 16:235-249. [PMID: 35094628 DOI: 10.1080/17474124.2022.2036122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) is a chronic, inflammatory condition that involves the intestinal tract, and can also present with extra-intestinal manifestations (EIM). Choosing the right treatment for IBD is often nuanced and decisions can become even more complicated when a patient presents with or develops a complication of the disease. AREAS COVERED We aimed to provide an overview of the most common complications of IBD, specifically intestinal and EIM, and summarize the data regarding biologic therapy for treatment of these conditions. A comprehensive literature review was performed using PubMed and Medline databases to identify studies published in the English language relevant to the broad scope of this review. EXPERT OPINION There are still significant gaps in our understanding of the pathophysiology of IBD and its treatment, especially in regards to complications of the disease. As novel therapies continue to emerge for treatment of IBD, we feel concurrent examination of their impact on intestinal complications and EIM of IBD is important and should be a priority of future research.
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Affiliation(s)
- Shana Rakowsky
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA USA
| | - Konstantinos Papamichael
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA USA
| | - Adam S Cheifetz
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA USA
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SEGURA MJ, ALÓS R, SOLANA A, ALARCÓN M, RUIZ MD, LOZOYA R. Autologous micro-fragmented fat injection results in cases of complex perianal fistula in patients with Crohn's disease. Chirurgia (Bucur) 2022. [DOI: 10.23736/s0394-9508.21.05271-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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D'Alessio S, Ungaro F, Noviello D, Lovisa S, Peyrin-Biroulet L, Danese S. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol 2022; 19:169-184. [PMID: 34876680 DOI: 10.1038/s41575-021-00543-0] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 12/11/2022]
Abstract
Intestinal fibrosis, which is usually the consequence of chronic inflammation, is a common complication of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. In the past few years, substantial advances have been made in the areas of pathogenesis, diagnosis and management of intestinal fibrosis. Of particular interest have been inflammation-independent mechanisms behind the gut fibrotic process, genetic and environmental risk factors (such as the role of the microbiota), and the generation of new in vitro and in vivo systems to study fibrogenesis in the gut. A huge amount of work has also been done in the area of biomarkers to predict or detect intestinal fibrosis, including novel cross-sectional imaging techniques. In parallel, researchers are embarking on developing and validating clinical trial end points and protocols to test novel antifibrotic agents, although no antifibrotic therapies are currently available. This Review presents the state of the art on the most recently identified pathogenic mechanisms of this serious IBD-related complication, focusing on possible targets of antifibrotic therapies, management strategies, and factors that might predict fibrosis progression or response to treatment.
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Affiliation(s)
| | - Federica Ungaro
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Daniele Noviello
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Sara Lovisa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,IBD Centre, Laboratory of Gastrointestinal Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Laurent Peyrin-Biroulet
- INSERM NGERE, University of Lorraine, Vandoeuvre-les-Nancy, Nancy, France.,Nancy University Hospital, Vandoeuvre-les-Nancy, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy. .,University Vita-Salute San Raffaele, Milan, Italy.
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The Fingerprints of Biomedical Science in Internal Medicine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:173-189. [DOI: 10.1007/5584_2022_729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
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Flap-Techniken – heute noch „State of the Art“? COLOPROCTOLOGY 2021. [DOI: 10.1007/s00053-021-00573-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Abstract
The long-held belief about adipose tissue was that it was relatively inert in terms of biological activity. It was believed that its primary role was energy storage; however, that was shattered with the discovery of adipokines. Scientists interested in regenerative medicine then reported that adipose tissue is rich in adult stromal/stem cells. Following these initial reports, adipose stem cells (ASCs) rapidly garnered interest for use as potential cellular therapies. The primary advantages of ASCs compared to other mesenchymal stem cells (MSCs) include the abundance of the tissue source for isolation, the ease of methodologies for tissue collection and cell isolation, and their therapeutic potential. Studies conducted both in vitro and in vivo have demonstrated that ASCs are multipotent, possessing the ability to differentiate into cells of mesodermal origins, including adipocytes, chondrocytes, osteoblast and others. Moreover, ASCs produce a broad array of cytokines, growth factors, nucleic acids (miRNAs), and other macromolecules into the surrounding milieu by secretion or in the context of microvesicles. The secretome of ASCs has been shown to alter tissue biology, stimulate tissue-resident stem cells, change immune cell activity, and mediate therapeutic outcomes. The quality of ASCs is subject to donor-to-donor variation driven by age, body mass index, disease status and possibly gender and ethnicity. This review discusses adipose stromal/stem cell action mechanisms and their potential utility as cellular therapeutics.
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Affiliation(s)
- Bruce A Bunnell
- Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Sebbagh AC, Rosenbaum B, Péré G, Alric H, Berger A, Wilhelm C, Gazeau F, Mathieu N, Rahmi G, Silva AKA. Regenerative medicine for digestive fistulae therapy: Benefits, challenges and promises of stem/stromal cells and emergent perspectives via their extracellular vesicles. Adv Drug Deliv Rev 2021; 179:113841. [PMID: 34175308 DOI: 10.1016/j.addr.2021.113841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/29/2021] [Accepted: 06/15/2021] [Indexed: 12/11/2022]
Abstract
Despite current management strategies, digestive fistulae remain extremely debilitating complications associated with significant morbidity and mortality, generating a need to develop innovative therapies in these indications. A number of clinical trials and experimental studies have thus investigated the potential of stem/stromal cells (SCs) or SC-derived extracellular vesicles (EVs) administration for post-surgical and Crohn's-associated fistulae. This review summarizes the physiopathology and current standards-of-care for digestive fistulae, along with relevant evidence from animal and clinical studies regarding SC or EV treatment for post-surgical digestive fistulae. Additionally, existing preclinical models of fistulizing Crohn's disease and results of SC therapy trials in this indication will be presented. The optimal formulation and administration protocol of SC therapy products for gastrointestinal fistula treatment and the challenges for a widespread use of darvadstrocel (Alofisel) in clinical practice will be discussed. Finally, the potential advantages of EV therapy and the obstacles towards their clinical translation will be introduced.
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Affiliation(s)
- Anna C Sebbagh
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France
| | - Boris Rosenbaum
- Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, Inserm UMR970, Paris Cardiovascular Research Center, Paris, France
| | - Guillaume Péré
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France; Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, Inserm UMR970, Paris Cardiovascular Research Center, Paris, France; Department of Digestive Surgery, Esogastric Bariatric and Endocrinal Surgery Unit, Toulouse-Rangueil University Hospital, Toulouse, France
| | - Hadrien Alric
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France; Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, Inserm UMR970, Paris Cardiovascular Research Center, Paris, France; Department of Gastroenterology and Endoscopy, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Arthur Berger
- Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, Inserm UMR970, Paris Cardiovascular Research Center, Paris, France
| | - Claire Wilhelm
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France
| | - Florence Gazeau
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France
| | - Noëlle Mathieu
- Human Health Department, SERAMED, LRMED, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France
| | - Gabriel Rahmi
- Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, Inserm UMR970, Paris Cardiovascular Research Center, Paris, France; Department of Gastroenterology and Endoscopy, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
| | - Amanda K A Silva
- Laboratoire Matière et Systèmes Complexes (MSC), Université de Paris/CNRS (UMR 7057), Paris, France.
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Ma J, Zhang Z, Wang Y, Shen H. Investigation of miR-126-3p loaded on adipose stem cell-derived exosomes for wound healing of full-thickness skin defects. Exp Dermatol 2021; 31:362-374. [PMID: 34694648 DOI: 10.1111/exd.14480] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 09/01/2021] [Accepted: 10/16/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To investigate the function of miR-126-3p loaded on adipose stem cell (ADSC)-derived exosomes (ADSC-Exos) in wound healing of full-thickness skin defects. METHODS ADSCs transfected with miR-126-3p mimic, miR-126-3p inhibitor or pcDNA3.1-PIK3R2, or PKH26-marked ADSC-Exos were cultured with fibroblasts or human umbilical vein endothelial cells (HUVECs). The proliferation and migration rates of fibroblasts and angiogenesis of HUVECs were measured. Rats with full-thickness skin defects were injected with ADSC-Exos or exosomes extracted from ADSCs transfected with miR-126-3p inhibitor and the wound healing rates were measured. The wound bed, collagen deposition and angiogenesis in injured rats were assessed. RESULTS ADSC-Exos could be ingested by fibroblasts and HUVECs. Co-incubation with ADSCs or ADSC-Exos promoted the proliferation and migration of fibroblasts and angiogenesis of HUVECs, which was further enhanced by miR-126-3p overexpression. Inhibition of ADSC-Exos or miR-126-3p or PIK3R2 overexpression suppressed the proliferation and migration of fibroblasts and angiogenesis of HUVECs. ADSC-derived exosomal miR-126-3p increased wound healing rate, collagen deposition and newly formed vessels in injured rats. CONCLUSION ADSC-derived exosomal miR-126-3p promotes wound healing of full-thickness skin defects by targeting PIK3R2.
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Affiliation(s)
- Jie Ma
- Department of Plastic Surgery, Shanghai General Hospital, Shanghai, 201620, P.R. China
| | - Zhaofeng Zhang
- Department of Plastic Surgery, Shanghai General Hospital, Shanghai, 201620, P.R. China
| | - Yinmin Wang
- Department of Plastic Surgery, Shanghai General Hospital, Shanghai, 201620, P.R. China
| | - Hua Shen
- Department of Plastic Surgery, Shanghai General Hospital, Shanghai, 201620, P.R. China
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Current Overview on the Use of Mesenchymal Stem Cells for Perianal Fistula Treatment in Patients with Crohn's Disease. Life (Basel) 2021; 11:life11111133. [PMID: 34833009 PMCID: PMC8622588 DOI: 10.3390/life11111133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/12/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Perianal fistula in patients with Crohn’s disease is an extremely challenging condition. The disease tends to reoccur, and with current treatment options, a large number of patients are left with active ailment and experience major morbidity. In recent years, hopeful results regarding local use of mesenchymal stem cells (MSCs) in perianal Crohn’s disease have been published. Although to this day there are no clear guidelines determining optimal dosage, injections frequency and culture conditions, their efficiency has proven to be much higher than conventionally used methods. According to studies, they can effectively induce as well as maintain fistula closure. This approach also avoids common side effects related to conventional surgical treatment.
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Improving the Efficacy of Mesenchymal Stem/Stromal-Based Therapy for Treatment of Inflammatory Bowel Diseases. Biomedicines 2021; 9:biomedicines9111507. [PMID: 34829736 PMCID: PMC8615066 DOI: 10.3390/biomedicines9111507] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/14/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) consisting of persistent and relapsing inflammatory processes of the intestinal mucosa are caused by genetic, environmental, and commensal microbiota factors. Despite recent advances in clinical treatments aiming to decrease inflammation, nearly 30% of patients treated with biologicals experienced drawbacks including loss of response, while others can develop severe side effects. Hence, novel effective treatments are highly needed. Mesenchymal stem/stromal cell (MSCs) therapy is an innovative therapeutic alternative currently under investigation for IBD. MSCs have the inherent capacity of modulating inflammatory immune responses as well as regenerating damaged tissues and are therefore a prime candidate to use as cell therapy in patients with IBD. At present, MSC-based therapy has been shown preclinically to modulate intestinal inflammation, whilst the safety of MSC-based therapy has been demonstrated in clinical trials. However, the successful results in preclinical studies have not been replicated in clinical trials. In this review, we will summarize the protocols used in preclinical and clinical trials and the novel approaches currently under investigation which aim to increase the beneficial effects of MSC-based therapy for IBD.
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Le Clainche T, Moisan A, Coll JL, Martel-Frachet V. The disc-shaped microcarriers: A new tool for increasing harvesting of adipose-derived mesenchymal stromal cells. Biochem Eng J 2021. [DOI: 10.1016/j.bej.2021.108082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Buscail E, Le Cosquer G, Gross F, Lebrin M, Bugarel L, Deraison C, Vergnolle N, Bournet B, Gilletta C, Buscail L. Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn's Disease: Rationale, Clinical Results and Perspectives. Int J Mol Sci 2021; 22:ijms22189967. [PMID: 34576129 PMCID: PMC8470328 DOI: 10.3390/ijms22189967] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/07/2021] [Accepted: 09/12/2021] [Indexed: 12/16/2022] Open
Abstract
Between 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures.
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Affiliation(s)
- Etienne Buscail
- Department of Surgery, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France;
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Guillaume Le Cosquer
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Fabian Gross
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Marine Lebrin
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Laetitia Bugarel
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
| | - Céline Deraison
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Nathalie Vergnolle
- IRSD, University of Toulouse, INSERM 1022, INRAe, ENVT, UPS, 31300 Toulouse, France; (C.D.); (N.V.)
| | - Barbara Bournet
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Cyrielle Gilletta
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
| | - Louis Buscail
- Department of Gastroenterology and Pancreatology, CHU Toulouse-Rangueil and Toulouse University, UPS, 31059 Toulouse, France; (G.L.C.); (B.B.); (C.G.)
- Centre for Clinical Investigation in Biotherapy, CHU Toulouse-Rangueil and INSERM U1436, 31059 Toulouse, France; (F.G.); (M.L.); (L.B.)
- Correspondence: ; Tel.: +33-561323055
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Debs T, Iannelli A, Frey S, Petrucciani N, Korkmaz C, Ben Amor V, Chenaitia H, Vanbiervliet G, Gugenheim J, Ben Amor I. Mesenchymal Stem Cells and Platelet Rich Plasma Therapy to Treat Leak After Sleeve Gastrectomy. J Surg Res 2021; 268:405-410. [PMID: 34416412 DOI: 10.1016/j.jss.2021.06.066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND One of the most feared and life-threatening complications after sleeve gastrectomy (SG) is staple line leak, with an incidence between 1 and 4%. Stable patients may be managed conservatively, with antibiotics, percutaneous drainage and endoscopy-based treatment. We propose mesenchymal stem cells (MSC) and platelet rich plasma (PRP) therapy as an innovative technique to treat leak after SG. MATERIAL AND METHODS Bone marrow MSCs is obtained by centrifugation of tibial puncture specimen. A peripheral whole blood sample is retrieved from the patient and centrifuged to obtain PRP. During endoscopy, the first 10 mL are injected in 4quadrants (equal volume) in the submucosae around the internal orifice. The second 10 mL are injected in the wall of the fistula tract. RESULTS The immediate course following the endoscopy was uneventful in both reported cases. The leaks healed in 30 and 42 D, respectively. Oral nutrition was progressively started during the third WK and fourth WK following the injection for both patients. No adverse event was noted during the follow-up period. CONCLUSION The management of fistulas post SG is controversial and actual available treatments present a relatively prolonged healing time. MSC administration retains a high potential value in the treatment of these fistulas. Further studies and wider clinical trials are mandatory to determine the impact of MSC administration.
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Affiliation(s)
- Tarek Debs
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
| | - Antonio Iannelli
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
| | - Sebastien Frey
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
| | - Niccolo Petrucciani
- Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy.
| | - Carine Korkmaz
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
| | | | | | | | - Jean Gugenheim
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
| | - Imed Ben Amor
- Digestive Surgery and Liver Transplantation Unit, University Hospital of Nice, Nice, France
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Pedersen KE, Lightner AL. Managing Complex Perianal Fistulizing Disease. J Laparoendosc Adv Surg Tech A 2021; 31:890-897. [PMID: 34314631 DOI: 10.1089/lap.2021.0285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Perianal disease is a particularly morbid phenotype of Crohn's disease, affecting up to one third of patients, with a significantly diminished quality of life. Conventional medical therapy and surgical interventions have limited efficacy. Medical treatment options achieve long-term durable remission in only a third of patients. Therefore, most patients undergo an operation, leaving them with a chronic seton or at risk of incontinence with multiple interventions. Mesenchymal stem cell therapy is an emerging therapy without risk of incontinence and improved efficacy as compared with conventional therapy. Laser therapy is another new intervention. Unfortunately, up to 40% of patients still require a stoma related to perianal fistulizing disease.
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Affiliation(s)
- Karina E Pedersen
- College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Park MY, Yoon YS, Lee JL, Park SH, Ye BD, Yang SK, Yu CS. Comparative perianal fistula closure rates following autologous adipose tissue-derived stem cell transplantation or treatment with anti-tumor necrosis factor agents after seton placement in patients with Crohn's disease: a retrospective observational study. Stem Cell Res Ther 2021; 12:401. [PMID: 34256838 PMCID: PMC8278611 DOI: 10.1186/s13287-021-02484-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background Perianal fistula is one of the most common complications in Crohn’s disease, and various medical and surgical treatments are being tried. The aim of this study was to compare the perianal fistula closure rates following treatment with anti-tumor necrosis factor (TNF) agents or autologous adipose tissue-derived stem cell (auto-ASC) transplantation with Crohn’s disease (CD). Methods CD patients who underwent seton placement for perianal fistula from January 2015 to December 2019 at a tertiary referral center were retrospectively reviewed. Patients were divided into two groups, one that received sequential treatments with anti-TNF agents (anti-TNF group) and the other that underwent auto-ASC transplantation (stem cell group). Clinical variables and fistula closure rates were compared in the two groups. Results Of the 69 patients analyzed, 39 were treated with anti-TNF agents and 30 underwent auto-ASC transplantation. Compared with the stem cell group, patients in the anti-TNF group were older (p=0.028), were more frequently male (p=0.019), had fistulas with more penetrating behavior (p=0.002), had undergone surgery more frequently (p=0.010), and had a shorter interval from seton placement to intended treatment (p<0.001). During a median follow-up of 46 months (range, 30–52.5 months), fistula closure rates were significantly faster (83.3% vs. 23.1%, p<0.001), and the mean interval from seton placement to fistula closure significantly shorter (14 vs. 37 months, p<0.001) in the stem cell than in the anti-TNF group. Three patients experienced fistula recurrence, all in the stem cell group. Conclusions Medical treatment using anti-TNF agents and auto-ASC transplantation are feasible treatment options after seton placement for Crohn’s perianal fistula. However, the closure rate was significantly faster and the time to closure significantly shorter in patients who underwent auto-ASC transplantation than medical treatment. Trial registration This study was retrospectively registered and approved by the Institutional Review Board of Asan Medical Center, number 2020-1059.
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Affiliation(s)
- Min Young Park
- Department of Colon and Rectal Surgery, Asan Medical Center, University of College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Yong Sik Yoon
- Department of Colon and Rectal Surgery, Asan Medical Center, University of College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
| | - Jong Lyul Lee
- Department of Colon and Rectal Surgery, Asan Medical Center, University of College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, Asan Medical Center, University of College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea
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MSC therapy for inflammatory bowel disease. КЛИНИЧЕСКАЯ ПРАКТИКА 2021. [DOI: 10.17816/clinpract64530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Inflammatory bowel disease (IBD) belongs to the group of diseases characterized by idiopathic inflammation of the digestive tract organs. Two basic IBD types are distinguished: ulcerative colitis and Crohns disease. The IBD symptoms including vomiting and diarrhea, abdominal pain, rectal bleeding, anemia have a significant negative impact on the general patients state of health. Besides, IBD patients are susceptible to the risk of a number of serious diseases such as colorectal cancer, thrombosis and primary sclerosing cholangitis. More than 4 million people in the USA and Europe suffer from IBD, with 70000 new cases diagnosed yearly in the USA only.
In some cases, a surgical removal of the damaged digestive tract fragments is required to treat severe IBD forms. However, drug therapy of IBD has mainly been used in the last decades. The rate of remission with application of traditional IBD therapy is estimated as 20-30%, and is still no higher than 50% with the combined therapy. Cell therapy has been proven to be a very promising approach in the IBD treatment. In our review, we discuss mesenchymal stromal cells (MSC) and the most important preclinical and clinical results of their application for the IBD therapy.
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Park MY, Yoon YS, Kim HE, Lee JL, Park IJ, Lim SB, Yu CS, Kim JC. Surgical options for perianal fistula in patients with Crohn's disease: A comparison of seton placement, fistulotomy, and stem cell therapy. Asian J Surg 2021; 44:1383-1388. [PMID: 33966965 DOI: 10.1016/j.asjsur.2021.03.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/16/2021] [Accepted: 03/14/2021] [Indexed: 10/21/2022] Open
Abstract
OBJECTIVE This study was designed to assess the demographic characteristics of patients with Crohn's perianal fistula (CPF) who were treated at a tertiary referral institution. Surgical outcomes were compared in groups of patients who underwent seton placement, fistulotomy, and stem cell therapy. METHODS Patients who underwent surgery for CPF between 2015 and 2017 at Asan Medical Center, Seoul, Korea, were retrospectively evaluated. Patients were divided into groups who underwent seton placement, fistulotomy, and stem cell therapy. Their clinical variables and closure rates were compared. RESULTS This study included 156 patients who underwent a total of 209 operations. More than half of the operations consisted of seton placement (67%), followed by stem cell therapy (18%) and fistulotomy (15%) patients. Of the 209 fistulas, 153 (73%) were complex, with an overall closure rate of 38% during a median follow-up of 29 months. Closure rates following fistulotomy, stem cell therapy, and seton placement were 90%, 70%, and 18%. Seton placement was more significantly frequently used than the other procedures in patients with complex fistula and those with abscesses. Of the 79 fistulas that achieved complete closure, 11 (14%) recurred. The recurrence rates did not differ among the various techniques. CONCLUSION Surgical treatment of CPF is dependent on lesion type. Seton placement was the primary draining procedure for complex fistulas and abscesses, resulting in low closure rates. Fistulotomy was the definite procedure for low type and simple fistula. Stem cell therapy showed high closure rates as definitive treatment, even for complex fistulas.
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Affiliation(s)
- Min Young Park
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong Sik Yoon
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Hyoung Eun Kim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jong Lyul Lee
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In Ja Park
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seok-Byung Lim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chang Sik Yu
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jin Cheon Kim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Regulatory Effect of Mesenchymal Stem Cells on T Cell Phenotypes in Autoimmune Diseases. Stem Cells Int 2021; 2021:5583994. [PMID: 33859701 PMCID: PMC8024100 DOI: 10.1155/2021/5583994] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/03/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Research on mesenchymal stem cells (MSCs) starts from the earliest assumption that cells derived from the bone marrow have the ability to repair tissues. Several scientists have since documented the crucial role of bone marrow-derived MSCs (BM-MSCs) in processes such as embryonic bone and cartilage formation, adult fracture and tissue repair, and immunomodulatory activities in therapeutic applications. In addition to BM-MSCs, several sources of MSCs have been reported to possess tissue repair and immunoregulatory abilities, making them potential treatment options for many diseases. Therefore, the therapeutic potential of MSCs in various diseases including autoimmune conditions has been explored. In addition to an imbalance of T cell subsets in most patients with autoimmune diseases, they also exhibit complex disease manifestations, overlapping symptoms among diseases, and difficult treatment. MSCs can regulate T cell subsets to restore their immune homeostasis toward disease resolution in autoimmune conditions. This review summarizes the role of MSCs in relieving autoimmune diseases via the regulation of T cell phenotypes.
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Tavares MMR, Barbosa LER. Adipose tissue-derived stem cells: a new approach to the treatment of Crohn's disease-associated perianal fistulae. JOURNAL OF COLOPROCTOLOGY 2021. [DOI: 10.1016/j.jcol.2018.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AbstractCrohn's disease has an ever-increasing prevalence and incidence, with about 20% of patients developing perianal fistula with significant impact on their quality of life.Despite the medical and surgical treatments currently used, Crohn's-related fistula treatment continues to pose a challenge due to the low rates of efficacy associated with high recurrence rates.Recent clinical trials have shown promising results regarding safety and efficacy of local treatment of this condition with the use of adipose tissue-derived mesenchymal stem cells. Besides being pluripotent and poorly immunogenic, they have immunomodulatory and anti-inflammatory properties, which combined, may accelerate healing.Our main objective is to summarize the clinical trials we found, highlighting the efficacy rates of this therapy and the main limitations we found in the analysis of the results.We conclude that, in perianal fistulas refractory to conventional therapies, the treatment with adipose tissue-derived mesenchymal cells is safe with promising results that may change the current paradigm of Crohn's related fistula treatment.
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Lee JL, Yoon YS, Yu CS. Treatment Strategy for Perianal Fistulas in Crohn Disease Patients: The Surgeon's Point of View. Ann Coloproctol 2021; 37:5-15. [PMID: 33730796 PMCID: PMC7989558 DOI: 10.3393/ac.2021.02.08] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Perianal fistula is a frequent complication and one of the subclassifications of Crohn disease (CD). It is the most commonly observed symptomatic condition by colorectal surgeons. Accurately classifying a perianal fistula is the initial step in its management in CD patients. Surgical management is selected based on the type of perianal fistula and the presence of rectal inflammation; it includes fistulotomy, fistulectomy, seton procedure, fistula plug insertion, video-assisted ablation of the fistulous tract, stem cell therapy, and proctectomy with stoma creation. Perianal fistulas are also managed medically, such as antibiotics, immunomodulators, and biologics including anti-tumor necrosis factor-alpha agents. The current standard treatment of choice for perianal fistula in CD patients is the multidisciplinary approach combining surgical and medical management; however, the rate of long-term remission is low and is reported to be 50% at most. Therefore, the optimum management strategy for perianal fistulas associated with CD remains controversial. Currently, the goal of management for CD-related perianal fistulas are controlling symptoms and maintaining long-term anal function without proctectomy, while monitoring progression to anorectal carcinoma. This review evaluates perianal fistula in CD patients and determines the optimal surgical management strategy based on recent evidence.
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Affiliation(s)
- Jong Lyul Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yong Sik Yoon
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Sik Yu
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Hou Q, Huang J, Ayansola H, Masatoshi H, Zhang B. Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases. Front Immunol 2021; 11:623691. [PMID: 33584726 PMCID: PMC7874163 DOI: 10.3389/fimmu.2020.623691] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.
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Affiliation(s)
- Qihang Hou
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Jingxi Huang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Hammed Ayansola
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
| | - Hori Masatoshi
- Department of Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition & Feed Science, College of Animal Science & Technology, China Agricultural University, Haidian District, Beijing, China
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