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Schwandner O. [Rectovaginal fistulas : Differentiated diagnostics and treatment]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:1027-1040. [PMID: 39283323 DOI: 10.1007/s00104-024-02151-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/22/2024] [Indexed: 11/26/2024]
Abstract
Rectovaginal fistulas (RVF) represent less than 5% of anorectal fistulas. The classification of RVF is based on the localization (low vs. high) and the etiology. The most frequent causes of RVF are birth trauma, Crohn's disease, previous surgery and pelvic irradiation. In most cases a clinical diagnostic assessment is sufficient. Additionally, endosonography is a reliable tool to detect sphincter defects. Computed tomography (CT) and magnetic resonance imaging (MRI) are reserved for special situations (e.g., RVF related to anastomotic leakage, after pelvic irradiation or associated with complex perianal fistulizing Crohn's disease). The surgical treatment is primarily oriented to the localization and etiology. Surgical techniques range from local procedures (e.g., endorectal advancement flap repair, transvaginal or transperineal closure) up to more invasive tissue interposition (e.g., bulbocavernosus muscle fat tissue flap or transposition of the gracilis muscle). In "high" RVF transabdominal approaches such as coloanal anastomosis, pull through procedures or omental interposition are indicated. All surgical procedures show high recurrence rates. Several operations are mostly necessary and a stoma creation is often required.
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Affiliation(s)
- Oliver Schwandner
- Abteilung für Proktologie, Krankenhaus Barmherzige Brüder Regensburg, Prüfeninger Str. 86, 93049, Regensburg, Deutschland.
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Kostecka A, Kalamon N, Skoniecka A, Koczkowska M, Skowron PM, Piotrowski A, Pikuła M. Adipose-derived mesenchymal stromal cells in clinical trials: Insights from single-cell studies. Life Sci 2024; 351:122761. [PMID: 38866216 DOI: 10.1016/j.lfs.2024.122761] [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: 04/02/2024] [Revised: 05/15/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024]
Abstract
Mesenchymal Stromal Cells (MSCs) offer tremendous potential for the treatment of various diseases and their healing properties have been explored in hundreds of clinical trials. These trails primarily focus on immunological and neurological disorders, as well as regenerative medicine. Adipose tissue is a rich source of mesenchymal stromal cells and methods to obtain and culture adipose-derived MSCs (AD-MSCs) have been well established. Promising results from pre-clinical testing of AD-MSCs activity prompted clinical trials that further led to the approval of AD-MSCs for the treatment of complex perianal fistulas in Crohn's disease and subcutaneous tissue defects. However, AD-MSC heterogeneity along with various manufacturing protocols or different strategies to boost their activity create the need for standardized quality control procedures and safety assessment of the intended cell product. High-resolution transcriptomic methods have been recently gaining attention, as they deliver insight into gene expression profiles of individual cells, helping to deconstruct cellular hierarchy and differentiation trajectories, and to understand cell-cell interactions within tissues. This article presents a comprehensive overview of completed clinical trials evaluating the safety and efficacy of AD-MSC treatment, together with current single-cell studies of human AD-MSC. Furthermore, our work emphasizes the increasing significance of single-cell research in elucidating the mechanisms of cellular action and predicting their therapeutic effects.
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Affiliation(s)
- Anna Kostecka
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Natalia Kalamon
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland.
| | - Aneta Skoniecka
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
| | - Magdalena Koczkowska
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Piotr M Skowron
- Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.
| | - Arkadiusz Piotrowski
- Faculty of Pharmacy, Medical University of Gdansk, Gdansk, Poland; 3P - Medicine Laboratory, Medical University of Gdansk, Gdansk, Poland.
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Faculty of Medicine, Medical University of Gdansk, Dębinki 1, 80-211 Gdańsk, Poland.
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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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Herreros MD, Ramirez JM, Otero-Piñeiro AM, Martí-Gallostra M, Badiola I, Enríquez-Navascues JM, Millan M, Barreiro EM, De La Portilla F, Suárez Alecha J, García-Olmo D. Use of Darvadstrocel (Allogenic Stem Cell Therapy) for Crohn's Fistulas in Real Clinical Practice: The National Project to Implement Mesenchymal Stem Cell for the Treatment of Perianal Crohn's Fistula (the PRIME Study). Dis Colon Rectum 2024; 67:960-967. [PMID: 38603800 DOI: 10.1097/dcr.0000000000003216] [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: 04/13/2024]
Abstract
BACKGROUND Perianal fistulas may affect 15% to 50% of patients with Crohn's disease. Treatment is complex, requiring a multidisciplinary approach. Darvadstrocel (allogenic mesenchymal cells obtained from lipoaspirates) was approved in 2018 by the European and Spanish Agencies of Medicines and Medical Products as a treatment for fistulas in Crohn's disease. Recent guidelines from the European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (n = 2). OBJECTIVE Presenting real-world effectiveness data for darvadstrocel in a Spanish population. DESIGN Observational retrospective cohort study with prospective data gathering. SETTINGS The study was conducted at 14 institutions in Spain. PATIENTS From November 2019 to April 2022, all patients (n = 73) treated with darvadstrocel in these institutions were included, fulfilling the following criteria: 1) complex fistula/s in a patient with Crohn's disease; 2) failure of conventional and antitumor necrosis factor treatment; and 3) the absence of collections of >2 cm confirmed by pelvic MRI at the time of surgery. INTERVENTIONS Darvadstrocel treatment. MAIN OUTCOME MEASURES Clinical response (closure of 50% or more of external openings), complete clinical closure (100% of external openings), and radiological closure (no fluid collection >2 cm, edema, or inflammation) evaluated 6 months after treatment. RESULTS Clinical response was observed in 63 patients (86.3%), complete clinical closure in 50 patients (68.5%), and radiological closure in 45 patients (69.2%). Combined clinical and radiological response was observed in 41 patients (63.1%). Not all clinically healed patients had radiological closure, and vice versa. No serious adverse events were reported. LIMITATIONS Retrospective nature of the study. CONCLUSIONS Study results were consistent with those reported in previous clinical trials, real-world efficacy findings from the INSPIRE study (assessing darvadstrocel effectiveness in Europe, Israel, Switzerland, United Kingdom, and Japan), and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for the treatment of fistulas in Crohn's disease. See Video Abstract . USO DE DARVADSTROCEL TERAPIA CON CLULAS MADRE ALOGNICAS PARA FSTULA EN ENFERMEDAD DE CROHN EN LA PRCTICA CLNICA REAL EL PROYECTO NACIONAL PARA IMPLEMENTAR DE CLULAS MADRE MESENQUIMALES PARA EL TRATAMIENTO DE LA FSTULA DE CROHN PERIANAL EL ESTUDIO PRIME ANTECEDENTES:Las fístulas perianales pueden afectar entre el 15 y el 50% de los pacientes con enfermedad de Crohn. El tratamiento es complejo y requiere un enfoque multidisciplinario. El darvadstrocel (células mesenquimales alogénicas obtenidas a partir de lipoaspirados) fue aprobado en 2018 por las Agencias Europea y Española de Medicamentos y Productos Sanitarios como tratamiento de las fístulas en la EC. Las recientes directrices de la Organización Europea de Crohn y Colitis y del Grupo de Trabajo Español sobre la Enfermedad de Crohn y Colitis Ulcerosa afirman que darvadstrocel es eficaz con un perfil de seguridad favorable y un sólido nivel de evidencia (2).OBJETIVO:Presentar datos de eficacia real de darvadstrocel en población española.DISEÑO:Estudio de cohorte retrospectivo observacional con recopilación prospectiva de datos.ESCENARIO:14 instituciones.PACIENTES:Desde noviembre de 2019 hasta abril de 2022, se incluyeron todos los pacientes (73) tratados con darvadstrocel en estas instituciones, que cumplieron los siguientes criterios: 1) fístula/s compleja/s en un paciente con enfermedad de Crohn; 2) fracaso del tratamiento convencional y anti factor de necrosis tumoral; 3) ausencia de colecciones > 2 cm confirmada por resonancia magnética pélvica en el momento de la cirugía.INTERVENCIONES:Tratamiento con Darvadstrocel.PRINCIPALES MEDIDAS DE RESULTADO:Respuesta clínica (cierre de ≥50% de las aberturas externas), cierre clínico completo (100% de las aberturas externas) y cierre radiológico (sin acumulación de líquido >2 cm, sin edema ni inflamación) evaluados 6 meses después del tratamiento.RESULTADOS:Se observó respuesta clínica en 63 pacientes (86.3%), cierre clínico completo en 50 pacientes (68.5%) y cierre radiológico en 45 pacientes (69.2%). Se observó respuesta clínica y radiológica combinada en 41 pacientes (63.1%). No todos los pacientes clínicamente curados tuvieron cierre radiológico y viceversa. No hubo eventos adversos graves reportados.LIMITACIONES:Estudio retrospectivoCONCLUSIONES:Los resultados del estudio fueron consistentes con los informados en ensayos clínicos anteriores, los hallazgos de eficacia en el mundo real del estudio INSPIRE (que evalúa la efectividad de darvadstrocel en Europa, Israel, Suiza, el Reino Unido y Japón) y la literatura publicada anteriormente. Darvadstrocel fue eficaz y demostró un perfil de seguridad favorable cuando se utiliza en la práctica clínica habitual para el tratamiento de fístulas en la enfermedad de Crohn. (Traducción-Dr. Jorge Silva Velazco ).
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Affiliation(s)
- Maria Dolores Herreros
- Department of Surgery, University Hospital Fundación Jiménez Díaz, Madrid, Spain
- New Therapy Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
| | - Jose-Manuel Ramirez
- Department of Surgery, University of Zaragoza, Zaragoza, Spain
- Spanish Multimodal Rehabilitation Group (GERM), Zaragoza, Spain
| | | | | | - Izaskun Badiola
- Department of Surgery University Hospital Galdakao-Usansolo, Vizcaya, Pais Vasco, Spain
| | | | - Monica Millan
- Department of Surgery, University Hospital la Fe, Valencia, Spain
| | - Erica M Barreiro
- Department of Surgery, University Hospital of Pontevedra, Galicia, Spain
| | | | | | - Damian García-Olmo
- Department of Surgery, University Hospital Fundación Jiménez Díaz, Madrid, Spain
- New Therapy Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
- Surgery Department, Universidad Autonoma de Madrid, Madrid, Spain
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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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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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Keung C, Nguyen TC, Lim R, Gerstenmaier A, Sievert W, Moore GT. Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up. EBioMedicine 2023; 98:104879. [PMID: 38042747 PMCID: PMC10755113 DOI: 10.1016/j.ebiom.2023.104879] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/29/2023] [Accepted: 11/03/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. METHODS A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. FINDINGS Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. INTERPRETATION Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. FUNDING This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.
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Affiliation(s)
- Charlotte Keung
- School of Clinical Sciences, Monash University, Australia; Department of Gastroenterology, Monash Health, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Australia.
| | | | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Australia
| | | | - William Sievert
- School of Clinical Sciences, Monash University, Australia; Department of Gastroenterology, Monash Health, Australia
| | - Gregory T Moore
- School of Clinical Sciences, Monash University, Australia; Department of Gastroenterology, Monash Health, Australia
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Li J, Ji Y, Chen N, Dai L, Deng H. Colitis-associated carcinogenesis: crosstalk between tumors, immune cells and gut microbiota. Cell Biosci 2023; 13:194. [PMID: 37875976 PMCID: PMC10594787 DOI: 10.1186/s13578-023-01139-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. One of the main causes of colorectal cancer is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). Intestinal epithelial cells (IECs), intestinal mesenchymal cells (IMCs), immune cells, and gut microbiota construct the main body of the colon and maintain colon homeostasis. In the development of colitis and colitis-associated carcinogenesis, the damage, disorder or excessive recruitment of different cells such as IECs, IMCs, immune cells and intestinal microbiota play different roles during these processes. This review aims to discuss the various roles of different cells and the crosstalk of these cells in transforming intestinal inflammation to cancer, which provides new therapeutic methods for chemotherapy, targeted therapy, immunotherapy and microbial therapy.
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Affiliation(s)
- Junshu Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Yanhong Ji
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Na Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Lei Dai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China.
| | - Hongxin Deng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, 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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Alinda MD, Christopher PM, Listiawan MY, Endaryanto A, Suroto H, Rantam FA, Hendradi E, Notobroto HB, Prakoeswa CRS. The efficacy of topical adipose mesenchymal stem cell-conditioned medium versus framycetin gauze dressing in chronic plantar ulcer of leprosy: A randomized controlled trial. Indian J Dermatol Venereol Leprol 2023; 89:656-664. [PMID: 36688887 DOI: 10.25259/ijdvl_784_2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 07/01/2022] [Indexed: 12/13/2022]
Abstract
Background Wound healing shows a unique interaction of several cells, growth factors and cytokines. The healing of chronic plantar ulcer of leprosy is influenced by various factors, one of which is the concentration of growth factors and cytokines related to the pathogenesis of impaired wound healing. Growth factors and cytokines can be found in the secretome of adipose mesenchymal stem cells. Aim To compare the effectiveness of topical adipose mesenchymal stem cell-conditioned medium and framycetin gauze dressing only on the healing of chronic plantar ulcer of leprosy. Methods In this randomised controlled trial, 32 patients with chronic plantar ulcer of leprosy were recruited. After detailed clinical and initial debridement, patients were randomised to two groups to receive either topical adipose mesenchymal stem cell-conditioned medium (n = 16) or framycetin gauze dressing only (n = 16) applied every three days for up to eight weeks, following which the ulcer size, adverse reactions and complications if any were monitored weekly. Results Healing percentage increased each week in all groups. Statistical differences between groups (P < 0.05) were observed from week 2 onwards for ulcer mean size reduction and from week 3 onwards for ulcer mean depth reduction. There were no adverse reactions or complications. Limitations Off-loading on subjects were not performed. Conclusion Adipose mesenchymal stem cell-conditioned medium is a potential therapeutic agent in the management of chronic plantar ulcer of leprosy.
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Affiliation(s)
- Medhi Denisa Alinda
- Post Graduate Doctoral Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
| | | | | | | | - Heri Suroto
- Department of Cell and Tissue Bank, Faculty of Medicine Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya, Jawa Timur, Indonesia
| | - Fedik Abdul Rantam
- Stem Cell Research and Development Center, Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
| | - Esti Hendradi
- Faculty of Pharmacy Universitas Airlangga, Surabaya, Jawa Timur, Indonesia
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Erceg Ivkošić I, Fureš R, Ćosić V, Mikelin N, Bulić L, Dobranić D, Brlek P, Primorac D. Unlocking the Potential of Mesenchymal Stem Cells in Gynecology: Where Are We Now? J Pers Med 2023; 13:1253. [PMID: 37623503 PMCID: PMC10455325 DOI: 10.3390/jpm13081253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/02/2023] [Accepted: 08/11/2023] [Indexed: 08/26/2023] Open
Abstract
Stem cells, with their remarkable capacity for differentiation into diverse cell types, are vital for the development as well as maintenance of health and homeostasis. Two unique abilities set them apart from other cells: self-renewal and the capacity for differentiation. They play important roles in embryogenesis, development, regeneration, and various other processes. Over the last decade, there has been increased interest in their potential use in the treatment of numerous diseases and disorders across multiple fields of medicine in acute, chronic, innate, and acquired diseases. Stem cells are key to maintaining the body's homeostasis and regulating growth and tissue functions. There are several types of stem cells-embryonic, adult, and human-induced pluripotent cells. Currently, mesenchymal stem cells are of great interest due to their regenerative, immunomodulatory, analgesic, and antimicrobial (anti-inflammatory) effects. Recent studies have shown the potent regenerative effect of stem cell therapy in gynecologic diseases such as infertility, Asherman syndrome, lichen sclerosus, polycystic ovary syndrome, premature ovarian insufficiency, genitourinary syndrome of menopause, and rectovaginal fistulas. Moreover, the successful isolation of oogonial stem cells could lead to a revolution in the field of gynecology and the potential treatment of the conditions discussed. This review aims to provide a better understanding of the latest therapeutic options involving stem cells and raise awareness of this promising yet not widely known topic in gynecology and medicine in general.
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Affiliation(s)
- Ivana Erceg Ivkošić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia (L.B.)
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Rajko Fureš
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Gynecology and Obstetrics, Zabok General Hospital and Croatian Veterans Hospital, 49210 Zabok, Croatia
| | - Vesna Ćosić
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Poliklinika Ćosić, d.o.o., 35000 Slavonski Brod, Croatia
| | - Nika Mikelin
- Health Center of the Zagreb County, 10000 Zagreb, Croatia
| | - Luka Bulić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia (L.B.)
| | | | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia (L.B.)
- School of Medicine, JJ Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia (L.B.)
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- School of Medicine, JJ Strossmayer University of Osijek, 31000 Osijek, Croatia
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Medical School, University of Split, 21000 Split, Croatia
- Eberly College of Science, The Pennsylvania State University, University Park, State College, PA 16802, USA
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96 450 Coburg, Germany
- Medical School, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
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12
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Garcia MF, Tiwari KK, Gendreau JL, Burgess PL, Taupin P, Martin ED. Mesenchymal Stem Cells and Regenerative Therapy with Bilateral Gracilis Flaps for Perineal Reconstruction of a Wound Infection in the Setting of Anal Squamous Cell Carcinoma. Adv Skin Wound Care 2023; 36:1-7. [PMID: 37471451 DOI: 10.1097/asw.0000000000000009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
ABSTRACT Many patients are affected by HIV/AIDS, and these conditions are highly prevalent worldwide. Patients with HIV/AIDS can experience debilitating wound infections that often require flap reconstruction and become challenging for surgeons to treat. In the past 5 years, mesenchymal stem cells have been tested and used as regenerative therapy to promote the growth of tissues throughout the body because of their ability to successfully promote cellular mitogenesis. To the authors' knowledge, the use of mesenchymal stem cell grafting following necrosis of a myocutaneous gracilis flap (as part of perineal wound reconstruction) has never been reported in the literature.In addition, the use of mesenchymal stem cells and regenerative medicine combined in the setting of squamous cell carcinoma of the anus with prior radiation (along with comorbid AIDS) has not been previously documented.In this report, the authors outline the case of a 60-year-old patient who had a recipient bed (perineum) complication from prior radiation therapy. Complicating the clinical picture, the patient also developed a Pseudomonal organ space infection of the pelvis leading to the failure of a vertical rectus abdominis myocutaneous flap and myocutaneous gracilis flaps. As a result, the patient underwent serial operative debridements for source control, with the application of mesenchymal stem cells, fetal bovine dermis, porcine urinary bladder xenograft, and other regenerative medicine products, achieving a highly successful clinical outcome. A procedural description for future use and replication of this method is provided.
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Affiliation(s)
- Matthew F Garcia
- At Dwight D. Eisenhower Army Medical Center, Fort Gordon, Georgia, USA, Matthew F. Garcia, MD, is Transitional Year Resident; Kirti K. Tiwari, MS, is Chief, Research Operations; Julian L. Gendreau, MD, is Transitional Year Resident; and Pamela L. Burgess, MD, is Chief, General Surgery. Philippe Taupin, PhD, is Senior Manager, Medical Affairs, Integra LifeSciences, Princeton, New Jersey. Also at Dwight D. Eisenhower Army Medical Center, Eric D. Martin, DO, is Chief, Cardiovascular Surgery. Dr Taupin is an employee of Integra LifeSciences Corporation. The authors have disclosed no other financial relationships related to this article. Submitted March 5, 2022; accepted in revised form September 9, 2022
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13
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García-Olmo D, Garcia-Arranz M. The history of Crohn's perianal fistula treatment with mesenchymal stem cells: the story of darvadstrocel. Expert Opin Biol Ther 2023; 23:1197-1202. [PMID: 37992074 DOI: 10.1080/14712598.2023.2274911] [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: 07/10/2023] [Accepted: 10/20/2023] [Indexed: 11/24/2023]
Abstract
INTRODUCTION This study provides an overview of the development of the first drug authorized for use in cell therapy. AREAS COVERED We analyze the case of darvadstrocel, an example of a successful cell-therapy drug used worldwide to treat Crohn's perianal fistula. A bibliographic-historical analysis of the first cellular treatment approved by the EMA, including relevant aspects concerning the authors, who were involved in the whole process. We would like to highlight the following messages: Development: The article describes the development process of the drug, from initial concept through the clinical trial phases. Learning from failure: In describing the development of darvadstrocel, the authors highlight the importance of learning from failures, which is crucial to achieving successful outcomes. Collaboration: The article underscores the need for collaboration between public and private institutions to facilitate the advancement of cell-therapy drugs and ensure efficiency while adhering to regulatory guidelines. EXPERT OPINION Regulatory requirements play a crucial role in the design and development of advanced therapies such as cell-therapy drugs. The findings of this study underscore the significance of appropriate disease application, meticulous donor selection, robust manufacturing processes, and proper therapy administration. Only by adopting these measures can cell-therapy drugs successfully complete all phases of the clinical trial process.
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Affiliation(s)
- Damian García-Olmo
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Mariano Garcia-Arranz
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain
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14
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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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Godoy-Brewer GM, Owodunni OP, Parian AM, Duraes LC, Selaru FM, Gearhart SL. Initial Clinical Outcomes Using Umbilical Cord-Derived Tissue Grafts to Repair Anovaginal Fistula. Dis Colon Rectum 2023; 66:299-305. [PMID: 35001050 DOI: 10.1097/dcr.0000000000002258] [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: 01/15/2023]
Abstract
BACKGROUND Perianal fistula is a debilitating disease and challenging condition to treat. Recently, the use of stem cells has been shown to improve healing of fistulas. OBJECTIVE The aim was to examine the use of an umbilical cord-derived stem cell graft in a pilot study as a novel scaffold/stem inlay implanted into fistula repairs for anovaginal fistula to examine healing rates. DESIGN This was a pilot study. SETTINGS This study took place in a colorectal surgery practice. PATIENTS Patients with anovaginal fistula consented to participate. Cryopreserved umbilical cord tissue graft with viable cells was incorporated as an inlay using a previously reported technique by the authors. Demographic data including history of previous repairs and IBD were included. All patients were followed for a minimum of 6 weeks. MAIN OUTCOME MEASURES The primary measures were safety and efficacy of novel stem cell graft in the treatment of anovaginal fistula. RESULTS From September 2017 to September 2019, 15 patients underwent anovaginal fistula repair. Three of these patients underwent a second repair, for a total of 18 repairs. No patient was intentionally diverted, but 3 patients presented for repair with a preexisting stoma. The majority of repairs were previous repair failures (12; 67%), and 7 repairs were performed on 5 patients with IBD. Median follow-up was 30 (6-104) weeks. The safety profile for cryopreserved umbilical cord tissue graft was excellent as no adverse events occurred. Overall complete healing rate was 39%, and 12 (67%) repairs resulted in improvement of symptoms. LIMITATIONS This was a small pilot study. CONCLUSIONS This is the largest series using cryopreserved umbilical cord graft for anovaginal fistula repair. The use of umbilical cord was safe and effective at closing defects. Randomized studies are necessary to determine added benefits over current standard of care. See Video Abstract at http://links.lww.com/DCR/B896 . RESULTADOS CLNICOS INICIALES DEL USO DE INJERTOS DE TEJIDO DERIVADO DE PLACENTA PARA REPARACIN DE FSTULAS ANOVAGINALES ANTECEDENTES:La fístula perianal es una enfermedad debilitante y una afección difícil de tratar. Recientemente, se ha demostrado que el uso de células madre mejora la curación de las fístulas.OBJETIVO:Deseamos examinar el uso de un injerto de células madre derivadas de cordón umbilical en un estudio piloto como una nueva matriz/injerto de células madre implantado en reparaciones de fístula para fístula anovaginal para examinar las tasas de curación.DISEÑO:Este fue un estudio piloto.ESCENARIO:Este estudio se llevó a cabo en una clínica de cirugía colorrectal.PACIENTES:Se obtuvo consentimiento informado de pacientes con fístula anovaginal. El injerto de tejido de cordón umbilical criopreservado con células viables se incorporó como incrustación utilizando una técnica previamente informada por los autores. Se incluyeron datos demográficos que incluían antecedentes de reparaciones previas y enfermedad inflamatoria intestinal. Todos los pacientes fueron seguidos durante un mínimo de 6 semanas.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas fueron la seguridad y la eficacia del nuevo injerto de células madre en el tratamiento de la fístula anovaginal.RESULTADOS:Desde 9/2017-9/2019, 15 pacientes fueron sometidas a reparación de fístula anovaginal. Tres de estos pacientes fueron sometidos a una segunda reparación, para un total de 18 reparaciones. Ningún paciente fue derivado intencionalmente mientras que 3 pacientes se presentaron para reparación con un estoma preexistente. La mayoría de las reparaciones fueron fallas de reparaciones previas (12, 67%) y se realizaron siete reparaciones en 5 pacientes con enfermedad inflamatoria intestinal (EII). La mediana de seguimiento fue de 30 semanas (6-104). El perfil de seguridad del injerto de tejido de cordón umbilical criopreservado fue excelente ya que no se produjeron efectos adversos. La tasa general de curación completa fue del 39% y 12 (67%) reparaciones dieron como resultado una mejoría de los síntomas.LIMITACIONES:Este fue un pequeño estudio piloto.CONCLUSIÓNES:Ésta es la serie más grande de utilización de injerto de cordón umbilical criopreservado para la reparación de una fístula anovaginal. La utilización del cordón umbilical resultó segura y eficaz para cerrar defectos. Se necesitan estudios aleatorizados para determinar los beneficios adicionales sobre el estándar de atención actual. Consulte Video Resumen en http://links.lww.com/DCR/B896 . (Traducción-Dr. Jorge Silva Velazco ).
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Affiliation(s)
- Gala M Godoy-Brewer
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | | | - Alyssa M Parian
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Leonardo C Duraes
- Division of Colorectal Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Florin M Selaru
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Susan L Gearhart
- Division of Colorectal Surgery, Johns Hopkins University, Baltimore, Maryland
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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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Burke CA, Park JE, Grisales T. Rectovaginal Fistula. FEMALE GENITOURINARY AND PELVIC FLOOR RECONSTRUCTION 2023:805-819. [DOI: 10.1007/978-3-031-19598-3_46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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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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El-Nakeep S, Shawky A, Abbas SF, Abdel Latif O. Stem cell transplantation for induction of remission in medically refractory Crohn's disease. Cochrane Database Syst Rev 2022; 5:CD013070. [PMID: 35556242 PMCID: PMC9099217 DOI: 10.1002/14651858.cd013070.pub2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Crohn's disease (CD) is an inflammatory bowel disease that causes inflammation and stricture, of any part of the mucosa and the gut wall. It forms skip lesions, sparing the areas in between the affected parts of the gastrointestinal tract. Crohn's disease could have one of three complications; fistula, intestinal obstruction due to stricture, or gastrointestinal inflammation presenting as severe diarrhoea. Stem cell therapy (SCT) is an innovative treatment that has been recently used in CD. The exact role of SCT in CD is still unclear. Stem cells modify the immunity of the patients or act as a "reset tool" for the immune system as in the case of systemically-injected stem cells, or regenerate the affected area of necrotic and inflammatory tissue as in the case of local injection into the lesion. Stem cells are a wide variety of cells including pluripotent stem cells or differentiated stem cells. The hazards range from rejection to symptomatic manifestations as fever or increase infection. OBJECTIVES: The objective of this Cochrane systematic review is to assess the effects of stem cell transplantation compared to standard of care alone or with placebo on efficacy and safety outcomes in patients with refractory CD. SEARCH METHODS We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and clinical trial registries (Clinicaltrials.gov, World Health Organization-International Clinical Trials Registry Platform WHO ICTRP) from inception to 19 March 2021, without any language, publication year, or publication status restrictions. In addition, we searched references of included studies and review articles for further references. An update of the published studies was done during the writing of the review. SELECTION CRITERIA We included only randomised controlled trials (RCTs) that assessed the effectiveness and safety of SCT in refractory CD versus standard care alone (control) or with placebo. DATA COLLECTION AND ANALYSIS Two review authors (SEN and SFA) independently screened the studies retrieved from the search results for inclusion, extracted data and assessed the risk of bias. Any disagreement was resolved through a consensus between the authors. We used standard methodological procedures expected by Cochrane. MAIN RESULTS We conducted our search on 19 March 2021 and identified 639 records. We added two records by a manual search of the published reviews on the topic to a total of 641 records. The Covidence program removed 125 duplicates making a total of 516 reports. Two review authors (SEN and SFA) screened titles and abstracts and excluded 451 records with the remaining 65 for full-text records screened independently by the two authors; only 18 studies were considered for inclusion. We included seven RCTs with a total of 442 participants for the meta-analysis. The intervention group included 234 patients, and the control group included 208 patients. Nine trials are ongoing and, two abstracts are awaiting classification. All patients in the control and intervention groups received the standard therapy for CD. Only three studies used blinding methods for the control group in the form of a placebo, with one study of the three stated that the blinding method was inefficient. The patients and personnel were aware of the intervention in the rest of the four studies as they were open-label trials. However, the effect of unblinding was balanced by the low risk of detection bias in five of the included studies. The evidence is uncertain about the effect of SCT on achieving clinical remission as compared to control/placebo (risk ratio (RR) 1.88, 95% Confidence Interval (CI) 0.80 to 4.41; 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT on achieving Crohn's Disease Activity Index (CDAI) <150 at 24 weeks compared to control (RR1.02 95% CI 0.67 to 1.56; 4 studies; very-low certainty evidence). SCT is likely to achieve fistula closure as compared to the control/placebo both in the short term (RR 1.48, 95% CI 1.12 to 1.96); low-certainty evidence) and in the long term (RR 1.42, 95% CI 1.09 to 1.87; 4 studies; low-certainty evidence) follow-up. The evidence is very uncertain about the effect of SCT to cause no difference in the number of total adverse events as compared to the control/placebo (RR 0.99, 95% CI [0.88 to 1.13); 4 studies; very-low-certainty evidence). However, SCT is likely to increase the number of serious adverse events as compared to the control/placebo (RR 1.22, 95% CI 0.88 to 1.67; 7 studies; low-certainty evidence). The evidence is very uncertain about the effect of SCT to decrease the withdrawal due to adverse events as compared to the control/placebo (RR 0.78, 95% CI 0.32 to 1.89; 3 studies; very-low certainty evidence). Funding by pharmaceutical companies was found in three studies, with one including more than 50% of our studied population. AUTHORS' CONCLUSIONS SCT shows an uncertain effect on clinical remission with low certainty of evidence. SCT shows an uncertain effect on CDAI score to reach <150 after 24 weeks of treatment, with very low certainty evidence. SCT shows beneficial effects on fistula-closure during short and long-term follow-up with low-certainty evidence in both outcomes. There was no change in the total number of adverse events with SCT as compared to control, with very low certainty evidence. While there was a moderate effect on increasing the number of serious adverse events in the SCT group, as compared to the control with low-certainty evidence. Withdrawal due to adverse events was slightly higher in the control group with very low certainty evidence. All the participants were refractory to standard medical treatment, but the number of participants was small, this may limit the generalizability of the results. Further research is needed for validation. More objective outcomes are needed in the assessment of stem cell effectiveness in the treatment of Crohn's disease, especially the intestinal CD subtype; with standardization of the dose, methods of stem cell preparation, route of administration, and inclusion criteria to the studies to achieve clear results.
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Affiliation(s)
- Sarah El-Nakeep
- Gastroenterology and Hepatology Unit, Internal Medicine Department , Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Shawky
- Gastroenterology and Hepatology Unit, Internal Medicine Department , Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Sara F Abbas
- Extended Medical Program, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Osama Abdel Latif
- Allergy and Clinical Immunology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Li F, Wu J, Li D, Hao L, Li Y, Yi D, Yeung KWK, Chen D, Lu WW, Pan H, Wong TM, Zhao X. Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy. J Nanobiotechnology 2022; 20:135. [PMID: 35292020 PMCID: PMC8922796 DOI: 10.1186/s12951-022-01347-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/02/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as "cell-free" therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. RESULTS In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. CONCLUSIONS In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy.
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Affiliation(s)
- Feiyang Li
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Jun Wu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, 999077, China
| | - Daiye Li
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, 999077, China
| | - Liuzhi Hao
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanqun Li
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Dan Yi
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Kelvin W K Yeung
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, 999077, China
| | - Di Chen
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - William W Lu
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, 999077, China
| | - Haobo Pan
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Tak Man Wong
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, 999077, China.
| | - Xiaoli Zhao
- Research Center for Human Tissue and Organs Degeneration, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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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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22
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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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Trébol J, Georgiev-Hristov T, Pascual-Miguelañez I, Guadalajara H, García-Arranz M, García-Olmo D. Stem cell therapy applied for digestive anastomosis: Current state and future perspectives. World J Stem Cells 2022; 14:117-141. [PMID: 35126832 PMCID: PMC8788180 DOI: 10.4252/wjsc.v14.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/21/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes.
AIM To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks.
METHODS PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words “anastomosis”, “colorectal/colonic anastomoses”, “anastomotic leak”, “stem cells”, “progenitor cells”, “cellular therapy” and “cell therapy” in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.
Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations.
RESULTS Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns.
CONCLUSION The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.
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Affiliation(s)
- Jacobo Trébol
- Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
- Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca 37007, Spain
| | - Tihomir Georgiev-Hristov
- Servicio de Cirugía General y del Aparato Digestivo, Hospital General Universitario de Villalba, Madrid 28400, Spain
| | - Isabel Pascual-Miguelañez
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario La Paz, Madrid 28046, Spain
| | - Hector Guadalajara
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Mariano García-Arranz
- Grupo de Investigación en Nuevas Terapias, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damian García-Olmo
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
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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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25
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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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Kent I, Freund MR, Agarwal S, Wexner SD. The application of regenerative medicine in colorectal surgery. Surgery 2021; 171:867-872. [PMID: 34649714 DOI: 10.1016/j.surg.2021.08.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/12/2021] [Accepted: 08/17/2021] [Indexed: 02/08/2023]
Abstract
Tissue reconstruction and regeneration represent one of the greatest challenges in any surgical field. Regenerative medicine combined with stem cell-based therapy is a novel and promising field of medicine. Stem cells possess the ability to differentiate into specialized cells and to decrease inflammation and therefore can play a role in repair or regeneration of damaged tissues. Colorectal surgery often deals with infected, poorly vascularized, radiated, and inflamed tissue, as well as instances where imperfect healing might have grave implications. This problem has led researchers to study utilizing stem cells in many colorectal conditions, such as anastomotic healing, perianal fistulae, rectovaginal fistulae, anal fissure, and fecal incontinence. The purpose of this review was to discuss prominent studies that explored stem cells utilization in treating different colorectal pathologies.
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Affiliation(s)
- Ilan Kent
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL. https://twitter.com/ilan_kent
| | - Michael R Freund
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL. https://twitter.com/mikifreund
| | - Samir Agarwal
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL. https://twitter.com/SamAgarwalMD1
| | - Steven D Wexner
- Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL.
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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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Lohsiriwat V, Jitmungngan R. Rectovaginal fistula after low anterior resection: Prevention and management. World J Gastrointest Surg 2021; 13:764-771. [PMID: 34512900 PMCID: PMC8394379 DOI: 10.4240/wjgs.v13.i8.764] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
Rectovaginal fistula after low anterior resection for rectal malignancy is one of the most challenging postoperative complications because it is difficult to treat and may complicate plans of adjuvant therapy. This problematic complication could lead to multiple operations, stoma formation, sexual dysfunction, fecal incontinence and psychosocial ramifications. This review comprehensively covers an overview of its incidence, risk factors, presentation and evaluation, management (ranging from conservative measures, endoscopic treatment and local tissue repair to radical resection and redo anastomosis) and treatment outcomes of rectovaginal fistula after low anterior resection. Notably, these therapeutic options and outcomes are influenced by several factors, including the size and location of the fistula, tumor clearance, cancer staging, quality of colorectal anastomosis and surrounding tissue, presence of diverting stoma, previous attempted repair, and the surgeon’s experience. Also, strategies to prevent rectovaginal fistula after low anterior resection are presented with illustrations. Finally, a decision-making algorithm for managing this complication is proposed.
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Affiliation(s)
- Varut Lohsiriwat
- Division of Colon and Rectal Surgery, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Romyen Jitmungngan
- Department of Surgery, The Golden Jubilee Medical Center, Mahidol University, Nakhon Pathom 73170, Thailand
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29
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Gui C, Parson J, Meyer GA. Harnessing adipose stem cell diversity in regenerative medicine. APL Bioeng 2021; 5:021501. [PMID: 33834153 PMCID: PMC8018797 DOI: 10.1063/5.0038101] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/26/2021] [Indexed: 12/20/2022] Open
Abstract
Since the first isolation of mesenchymal stem cells from lipoaspirate in the early 2000s, adipose tissue has been a darling of regenerative medicine. It is abundant, easy to access, and contains high concentrations of stem cells (ADSCs) exhibiting multipotency, proregenerative paracrine signaling, and immunomodulation-a winning combination for stem cell-based therapeutics. While basic science, preclinical and clinical findings back up the translational potential of ADSCs, the vast majority of these used cells from a single location-subcutaneous abdominal fat. New data highlight incredible diversity in the adipose morphology and function in different anatomical locations or depots. Even in isolation, ADSCs retain a memory of this diversity, suggesting that the optimal adipose source material for ADSC isolation may be application specific. This review discusses our current understanding of the heterogeneity in the adipose organ, how that heterogeneity translates into depot-specific ADSC characteristics, and how atypical ADSC populations might be harnessed for regenerative medicine applications. While our understanding of the breadth of ADSC heterogeneity is still in its infancy, clear trends are emerging for application-specific sourcing to improve regenerative outcomes.
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Affiliation(s)
- Chang Gui
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63110, USA
| | - Jacob Parson
- Program in Physical Therapy, Washington University in St. Louis, St. Louis, Missouri 63110, USA
| | - Gretchen A. Meyer
- Author to whom correspondence should be addressed:. Tel.: (314) 286-1425. Fax: (314) 747-0674
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30
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Lansdorp CA, Buskens CJ, Gecse KB, D'Haens GRAM, van Hulst RA. Hyperbaric oxygen therapy for the treatment of rectovaginal fistulas in patients with Crohn's disease: results of the HOT-REVA pilot study. BJS Open 2021; 5:6287303. [PMID: 34046674 PMCID: PMC8160532 DOI: 10.1093/bjsopen/zrab042] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/14/2021] [Indexed: 12/16/2022] Open
Abstract
Background Positive effects of hyperbaric oxygen (HBO) on perianal fistulas in Crohn’s disease (CD) have been described, but the effect on rectovaginal fistulas (RVFs) has not yet been studied. The aim was to investigate the efficacy, safety and feasibility of HBO in patients with RVF in CD. Methods In this prospective study, consecutive CD patients between November 2018 and February 2020 presenting with RVF at the outpatient fistula clinic of the Amsterdam University Medical Centre were included and selected to receive treatment with 30 daily HBO sessions, if fistulas were actively draining and any concomitant treatment regimen was stable at least 6 weeks prior to start of HBO. Patients with a stoma were excluded. The primary endpoint was clinical closure at 3-month follow-up, defined as cessation of complaints and/or closure of the external orifice if visible at baseline. Secondary outcomes were improvement of concomitant perianal fistulas as measured by the perianal disease activity index (PDAI) and fistula drainage assessment (FDA), as well as improvement in patient-reported outcomes (visual analogue scale (VAS), inflammatory bowel disease questionnaire (IBDQ), faecal incontinence quality of life scale (FIQL) and female sexual functioning index (FSFI)) at 3-month follow-up. Results Out of 14 eligible patients, nine patients (median age 50 years) were treated, all of whom had previously had one or more unsuccessful medical and/or surgical treatments for their RVF. Clinical closure occurred in none of the patients at 3-month follow-up. There was no improvement in PDAI and patient-reported outcomes (VAS, IBDQ, FIQL and FSFI). Two patients had concomitant perianal fistulas; using FDA, one patient had a clinical response and one patient was in clinical remission 3 months after HBO. There were two treatment-related adverse events during HBO concerning claustrophobia and fatigue. Furthermore, two patients had a surgical intervention due to RVF and two patients were treated with antibiotics for a urinary tract infection during follow-up. One patient had a dose reduction of ustekinumab because of decreased luminal complaints. Conclusion Treatment with HBO was feasible, but in this therapy-refractory cohort without deviating ostomy no clinical closure of RVF or improvement in quality of life was seen 3 months after HBO. Treatment with HBO alone in this specific group of patients therefore appears to be ineffective.
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Affiliation(s)
- C A Lansdorp
- Department of Anaesthesiology/Hyperbaric Medicine, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
| | - C J Buskens
- Department of Surgery, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
| | - K B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
| | - G R A M D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
| | - R A van Hulst
- Department of Anaesthesiology/Hyperbaric Medicine, Amsterdam University Medical Centre, location AMC, Amsterdam, the Netherlands
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31
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Rectoneovaginal fistula after sex reassignment surgery. Description of our experience and literature review. Actas Urol Esp 2021; 45:239-244. [PMID: 33139068 DOI: 10.1016/j.acuro.2020.08.012] [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: 07/11/2020] [Accepted: 08/22/2020] [Indexed: 11/20/2022]
Abstract
Male-to-female reassignment surgery or vaginoplasty includes those surgical procedures that aim to recreate a functional and cosmetically acceptable female perineum with minimal scarring. The technique of choice at our center is penile inversion vaginoplasty with or without scrotal skin grafts. We present 4 cases diagnosed with rectoneovaginal fistulas treated at our center with favorable evolution. The first patient was diagnosed in the late postoperative period during dilation. She underwent 2 failed vaginal repair attempts. Finally, a temporary colostomy and a rectal flap were performed. The second patient was diagnosed 2 weeks after the initial surgery due to aggressive dilation and was treated with a temporary colostomy and secondary wound closure. The third patient was diagnosed on the fifth post-operative day after removal of the vaginal packing. Dietary restriction was indicated, and a rectal flap was performed. A fourth patient was diagnosed within the late postoperative period; she was submitted to surgical exploration and a rectal wall flap was created. Rectoneovaginal fistulas after sex reassignment surgery has an incidence of about 2-17% and they are the most common type of fistula after this procedure. In most cases, it is secondary to rectal injury during the initial surgery. The management of these fistulas ranges from primary closure, diverting colostomies, conservative management, or the performance of flaps. A multidisciplinary team approach is recommended for the diagnosis and treatment of this complication.
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32
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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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33
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Al-Ghadban S, Bunnell BA. Adipose Tissue-Derived Stem Cells: Immunomodulatory Effects and Therapeutic Potential. Physiology (Bethesda) 2021; 35:125-133. [PMID: 32027561 DOI: 10.1152/physiol.00021.2019] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ASCs) can self-renew and differentiate along multiple cell lineages. ASCs are also potently anti-inflammatory due to their inherent ability to regulate the immune system by secreting anti-inflammatory cytokines and growth factors that play a crucial role in the pathology of many diseases, including multiple sclerosis, diabetes mellitus, Crohn's, SLE, and graft-versus-host disease. The immunomodulatory effects and mechanisms of action of ASCs on pathological conditions are reviewed here.
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Affiliation(s)
- Sara Al-Ghadban
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Bruce A Bunnell
- Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana.,Department of Pharmacology, School of Medicine, Tulane University, New Orleans, Louisiana
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34
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Efficacy and Safety of Mesenchymal Stem/Stromal Cell Therapy for Inflammatory Bowel Diseases: An Up-to-Date Systematic Review. Biomolecules 2021; 11:biom11010082. [PMID: 33440772 PMCID: PMC7827559 DOI: 10.3390/biom11010082] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been demonstrated to be safe and effective for perianal fistulizing Crohn’s disease (PFCD). This systematic review aims to present the most recent studies on the safety and efficacy of MSC therapy in IBD. A detailed search strategy of clinical trials on MSCs and IBD was performed on PubMed, with 32 studies selected for inclusion in this review. The newest studies on local MSC injection for PFCD continue to support long-term efficacy while maintaining a favorable safety profile. The evidence for systemic MSC infusion in luminal IBD remains mixed due to marked methodological heterogeneity and unclear safety profiles. Although further studies are needed to better establish the role of this novel treatment modality, MSCs are proving to be a very exciting addition to the limited therapies available for IBD.
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35
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Cao Y, Su Q, Zhang B, Shen F, Li S. Efficacy of stem cells therapy for Crohn's fistula: a meta-analysis and systematic review. Stem Cell Res Ther 2021; 12:32. [PMID: 33413661 PMCID: PMC7792029 DOI: 10.1186/s13287-020-02095-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Fistulas have puzzled us all the time and stem cell therapy for it is still in its infancy. We conducted a meta-analysis and systematic review to evaluate the efficacy of stem cells and its potential mechanisms in the management of Crohn's fistula. METHODS Electronic databases were searched comprehensively for studies reporting the efficacy and safety of stem cells in patients with any form of Crohn's fistula. A random-effects model was used, and all outcomes were calculated by SPSS 24.0. RESULTS Twenty-nine articles with 1252 patients were included. It showed that stem cell group had a higher rate of fistula healing compared to placebo group in patients of Crohn's fistula (61.75% vs 40.46%, OR 2.21, 95% CI 1.19 to 4.11, P < 0.05). 3 × 107 cells/mL stem cell (SC) group had an advantage in fistula healing rate with 71.0% compared to other doses group of stem cells (RR 1.3, 95% CI 0.76 to 2.22). And the healing rates of patients with perianal and transsphincteric fistulas (77.95%, 76.41%) were higher than those with rectovaginal fistulas. It was an amazing phenomenon that CDAI and PDAI scores occurred an obviously transient rise with the use of stem cells after 1 month (both of P < 0.05), while they returned to the baseline level by giving stem cells 3 months later. Furthermore, the incidence rate of treatment-related adverse events in the stem cell group was significantly lower than in the placebo group (RR 0.58, 95% CI 0.30 to 1.14). CONCLUSIONS Our study has highlighted that stem cells was a promising method in the treatment of Crohn's fistula based on its higher efficacy and lower incidence of adverse events, especially ADSCs and Cx601. While it also needs more clinical and pre-clinical studies to strengthen evidences in the future.
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Affiliation(s)
- Yantian Cao
- Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Hua Lan Avenue, Xinxiang, 453003, Henan Province, China
| | - Qi Su
- Department of General surgery, The Third Affiliated Hospital of Xinxiang Medical University, Hua Lan Avenue, Xinxiang, 453003, Henan Province, China
| | - Bangjie Zhang
- Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Hua Lan Avenue, Xinxiang, 453003, Henan Province, China
| | - Fangfang Shen
- The Key Laboratory for Tumor Translational Medicine, The Third Affiliated Hospital of Xinxiang Medical University, Hua Lan Avenue, Xinxiang, 453003, Henan Province, China
| | - Shaoshan Li
- Department of General surgery, The Third Affiliated Hospital of Xinxiang Medical University, Hua Lan Avenue, Xinxiang, 453003, Henan Province, China.
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36
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Nikolic M, Stift A, Reinisch W, Vogelsang H, Matic A, Müller C, von Strauss Und Torney M, Riss S. Allogeneic expanded adipose-derived stem cells in the treatment of rectovaginal fistulas in Crohn's disease. Colorectal Dis 2021; 23:153-158. [PMID: 32810356 PMCID: PMC7891611 DOI: 10.1111/codi.15324] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022]
Abstract
AIM Crohn's disease (CD)-related rectovaginal fistulas (RVFs) are rare, challenging to treat and associated with a high morbidity. Due to a significant lack of data, we aimed to analyse the safety and feasibility of allogeneic adipose-derived stem cells (ASCs) in the treatment of CD-related RVF. METHOD Four consecutive patients with CD-related RVF underwent treatment with expanded allogeneic ASCs extracted from a healthy donor in a tertiary referral centre in 2019. None of the patients had an intestinal diversion at the time of the treatment. Follow-up was performed 6 months postoperatively. RESULTS The median operation time was 45 min with a median hospital stay of 3 days. No intra-operative complications occurred. Three patients (75%) developed recurrent RVF after a median follow-up of 19 days. Two patients required surgical treatment including loose seton drainage due to discharge and pain. One patient developed recurrence of symptoms after 10 days, but refused further surgical therapy. Only one patient (25%) showed healing of the RVF, with re-epithelialization of both the vaginal and rectal opening and absence of clinical symptoms. CONCLUSION Expanded allogeneic ASC therapy represents a novel safe treatment option for CD-associated RVF. Although efficacy appears limited, further controlled studies are required to draw robust conclusions.
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Affiliation(s)
- M Nikolic
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - A Stift
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - W Reinisch
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - H Vogelsang
- Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - A Matic
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - C Müller
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - M von Strauss Und Torney
- Department of Visceral Surgery, St Clara Hospital and University Hospital Basel, Clarunis University Centre for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - S Riss
- Department of Surgery, Medical University of Vienna, Vienna, Austria
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37
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McDermott FD. Allogeneic expanded adipose-derived stem cells in the treatment of rectovaginal fistulas in Crohn's disease, by Nikolic et al. Colorectal Dis 2021; 23:4. [PMID: 33501776 DOI: 10.1111/codi.15508] [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: 02/08/2023]
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38
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Silva Couto P, Rotondi M, Bersenev A, Hewitt C, Nienow A, Verter F, Rafiq Q. Expansion of human mesenchymal stem/stromal cells (hMSCs) in bioreactors using microcarriers: lessons learnt and what the future holds. Biotechnol Adv 2020; 45:107636. [DOI: 10.1016/j.biotechadv.2020.107636] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 08/01/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023]
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39
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CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2020; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.
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40
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Sarnik SA, Sutermaster BA, Darling EM. Mass-Added Density Modulation for Sorting Cells Based on Differential Surface Protein Levels. Cytometry A 2020; 99:488-495. [PMID: 32687243 DOI: 10.1002/cyto.a.24192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/23/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022]
Abstract
Cell sorting is a powerful tool in basic research and therapeutic enrichment. However, common cell sorting methods, such as fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) have significant limitations, such as generally low cell yields or restriction to binary separation, respectively. To address these limitations, we developed a two-step cell sorting method called mass-added density centrifugation (MADC) to enable nonbinary separation of large cell numbers based on surface protein levels. In the first MADC step (mass-adding), antibody-directed massive microparticles bind target surface proteins to modulate single-cell density proportionally to target protein level. Second, microparticle-laden cells are subjected to discontinuous density gradient centrifugation, whereby they separate into discrete density bands which can be isolated for downstream use. MADC will prove especially advantageous for obtaining sufficient cell numbers for protein analyses from large source populations, and it is a fast process that can facilitate live cell enrichment for therapies that require tens of millions of cells. Here, we demonstrate MADC's utility for both live and fixed cell sorts of multiple cell types based on abundance of an example target protein, CD44. CD44 quantity in separated cell groups was assayed with western blots and correlated with modulated cell density. This novel sorting method enables rapid, nonbinary isolation of large quantities of cells based on surface protein levels and should prove useful in both basic science and therapeutic applications. © 2020 International Society for Advancement of Cytometry.
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Affiliation(s)
- Sylvia A Sarnik
- Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA
| | - Bryan A Sutermaster
- Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA
| | - Eric M Darling
- Center for Biomedical Engineering, Brown University, Providence, Rhode Island, USA.,Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, Rhode Island, USA.,School of Engineering, Brown University, Providence, Rhode Island, USA.,Department of Orthopaedics, Brown University, Providence, Rhode Island, USA
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41
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Barnhoorn MC, Hakuno SK, Bruckner RS, Rogler G, Hawinkels LJAC, Scharl M. Stromal Cells in the Pathogenesis of Inflammatory Bowel Disease. J Crohns Colitis 2020; 14:995-1009. [PMID: 32160284 PMCID: PMC7392167 DOI: 10.1093/ecco-jcc/jjaa009] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Up till now, research on inflammatory bowel disease [IBD] has mainly been focused on the immune cells present in the gastrointestinal tract. However, recent insights indicate that stromal cells also play an important and significant role in IBD pathogenesis. Stromal cells in the intestines regulate both intestinal epithelial and immune cell homeostasis. Different subsets of stromal cells have been found to play a role in other inflammatory diseases [e.g. rheumatoid arthritis], and these various stromal subsets now appear to carry out also specific functions in the inflamed gut in IBD. Novel potential therapies for IBD utilize, as well as target, these pathogenic stromal cells. Injection of mesenchymal stromal cells [MSCs] into fistula tracts of Crohn's disease patients is already approved and used in clinical settings. In this review we discuss the current knowledge of the role of stromal cells in IBD pathogenesis. We further outline recent attempts to modify the stromal compartment in IBD with agents that target or replace the pathogenic stroma.
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Affiliation(s)
- M C Barnhoorn
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands,Corresponding author: Prof. Dr Michael Scharl, Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, Zurich 8091, Switzerland. Tel: 41 44 255 3419; Fax: 41 44 255 9497;
| | - S K Hakuno
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - R S Bruckner
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands,Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - G Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - L J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - M Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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42
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Challenges in Crohn's disease: Complex perianal Crohn's disease. SEMINARS IN COLON AND RECTAL SURGERY 2020. [DOI: 10.1016/j.scrs.2020.100747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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43
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Spinelli A, Armuzzi A, Ciccocioppo R, Danese S, Gionchetti P, Luglio G, Orlando A, Rispo A, Rizzello F, Sofo L, Solina G, Poggioli G. Management of patients with complex perianal fistulas in Crohn's disease: Optimal patient flow in the Italian clinical reality. Dig Liver Dis 2020; 52:506-515. [PMID: 31901310 DOI: 10.1016/j.dld.2019.11.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 11/07/2019] [Accepted: 11/18/2019] [Indexed: 12/11/2022]
Abstract
Perianal fistulizing Crohn's disease (PFCD) is a common, disabling and aggressive phenotype that negatively impacts on the quality of life of affected patients. Its successful treatment is still a struggle for both physicians and patients. Significant advances in the management of this condition have occurred in the last two decades holding promise for a better future. This culminated into the concept of a collaborative multidisciplinary approach using the latest medical therapies combined with modern surgical and endoscopic techniques. Despite this, PFCD management and treatment have not been standardized yet. Thus the gastroenterologist and surgeon have to be familiar with several approaches and/or techniques. The positioning of each therapeutic option will certainly evolve with new data, but for the time being it should be driven by patient's characteristics, physician's preference and/or experience, costs and availability in local practice. Additionally, patient's perception of benefits and risks of treatment may differ from those of physicians and recognition of this difference is a starting point for difficult clinical decision-making. In this paper, a multidisciplinary group of Italian IBD experts explore and discuss current medical and surgical therapeutic options, highlighting areas of unmet needs in PFCD, with particular focus on the optimal patient flow within the Italian clinical reality.
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Affiliation(s)
- Antonino Spinelli
- Division of Colon and Rectal Surgery, Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
| | | | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, G.B. Rossi University Hospital, Verona, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy; IBD Center, Humanitas Clinical and Research Hospital, Rozzano, Milan, Italy
| | - Paolo Gionchetti
- Emilia-Romagna IBD Regional Referral Center, Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Gaetano Luglio
- Surgery Unit, Department of Public Health, Federico II University Hospital, Naples, Italy
| | | | - Antonio Rispo
- Gastroenterology Unit, Federico II University Hospital, Naples, Italy
| | - Fernando Rizzello
- Emilia-Romagna IBD Regional Referral Center, Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Luigi Sofo
- Abdominal SUrgery Unit, Department of Gastroenterology, Endocrine-metabolic and Nephrourological Science, A. Gemelli Hospital, Cattolica University, Rome, Italy
| | - Gaspare Solina
- Unit of General and Oncological Surgery, Department of Surgery, "Villa Sofia-Cervello" Hospital, Palermo, Italy
| | - Gilberto Poggioli
- Digestive Surgery Department, S. Orsola-Malpighi University Hospital, Bologna, Italy
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44
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Lightner AL, Dozois EJ, Dietz AB, Fletcher JG, Friton J, Butler G, Faubion WA. Matrix-Delivered Autologous Mesenchymal Stem Cell Therapy for Refractory Rectovaginal Crohn's Fistulas. Inflamm Bowel Dis 2020; 26:670-677. [PMID: 31605115 DOI: 10.1093/ibd/izz215] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Crohn's rectovaginal fistulizing disease remains notoriously difficult to treat. A phase I clinical trial to evaluate the safety and feasibility of a novel protocol using a mesenchymal stem cell (MSC)-coated Gore Bio-A fistula plug for the treatment of medically and surgically refractory Crohn's rectovaginal fistulas was conducted. METHODS Five patients underwent an autologous subcutaneous adipose tissue harvest via a 2-cm abdominal wall incision at time of exam under anesthesia (EUA) with seton placement. MSCs were isolated, expanded, and impregnated on the plug. After 6 weeks, patients returned to the operating room for placement of the MSC-coated plug. The primary end points were safety and feasibility; the secondary end point was clinical and radiographic healing at 6 months. RESULTS Five female patients (median age [range], 49 [38-53] years) with a median disease duration (range) of 23 (7-34) years who were on biologic (n = 5) or combination therapy (n = 3) had successful harvest and expansion of MSCs and delivery of the Gore Bio-A plug. There were no serious adverse events or adverse events related to the MSCs or plug during the 6-month follow-up. At 6 months, 3 patients had complete cessation of drainage, and 2 had >50% reduction in drainage; all had a persistent fistula tract identified on magnetic resonance imaging and EUA at 6 months. CONCLUSIONS Surgical placement of an autologous adipose-derived MSC-coated fistula plug in diverted patients with Crohn's rectovaginal fistulas was safe and feasible. All patients had a reduction in the size of their fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing.This was a phase I clinical trial of autologous mesenchymal stem cells on a plug for rectovaginal Crohn's fistulas.
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Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Eric J Dozois
- Division of Colon and Rectal Surgery, Rochester, Minnesota, USA
| | - Allan B Dietz
- IMPACT Lab, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Rochester, Minnesota, USA
| | | | - Jessica Friton
- Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | - Greg Butler
- IMPACT Lab, Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Rochester, Minnesota, USA
| | - William A Faubion
- Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
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The Achievements and Challenges of Mesenchymal Stem Cell-Based Therapy in Inflammatory Bowel Disease and Its Associated Colorectal Cancer. Stem Cells Int 2020; 2020:7819824. [PMID: 32256612 PMCID: PMC7104387 DOI: 10.1155/2020/7819824] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/07/2020] [Accepted: 02/03/2020] [Indexed: 02/08/2023] Open
Abstract
Approximately 18.1 × 106 new cases of cancer were recorded globally in 2018, out of which 9.6 million died. It is known that people who have Inflammatory Bowel Disease (IBD) turn to be prone to increased risks of developing colorectal cancer (CRC), which has global incident and mortality rates of 10.2% and 9.2%, respectively. Over the years, conventional treatments of IBD and its associated CRC have been noted to provide scarce desired results and often with severe complications. The introduction of biological agents as a better therapeutic approach has witnessed a great deal of success in both experimental and clinical models. With regard to mesenchymal stem cell (MSC) therapy, the ability of these cells to actively proliferate, undergo plastic differentiation, trigger strong immune regulation, exhibit low immunogenicity, and express abundant trophic factors has ensured their success in regenerative medicine and immune intervention therapies. Notwithstanding, MSC-based therapy is still confronted with some challenges including the likelihood of promoting tumor growth and metastasis, and possible overestimated therapeutic potentials. We review the success story of MSC-based therapy in IBD and its associated CRC as documented in experimental models and clinical trials, examining some of the challenges encountered and possible ways forward to producing an optimum MSC therapeutic imparts.
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Therapeutic Effects of Mesenchymal Stem Cells Derived From Bone Marrow, Umbilical Cord Blood, and Pluripotent Stem Cells in a Mouse Model of Chemically Induced Inflammatory Bowel Disease. Inflammation 2020; 42:1730-1740. [PMID: 31227956 DOI: 10.1007/s10753-019-01033-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Acute inflammatory bowel disease (AIBD) is a wide clinical entity including severe gastrointestinal pathologies with common histopathological basis. Epidemiologically increasing diseases, such as necrotizing enterocolitis (NEC), gastrointestinal graft versus host disease (GVHD), and the primary acute phase of chronic inflammatory bowel disease (CIBD), exhibit a high necessity for new therapeutic strategies. Mesenchymal stem cell (MSC) cellular therapy represents a promising option for the treatment of these diseases. In our study, we comparatively assess the efficacy of human MSCs derived from bone marrow (BM), umbilical cord blood (UCB), human embryonic stem cells (ESCs), or human-induced pluripotent stem cells (iPSCs) in a mouse model of chemically induced acute enterocolitis. The laboratory animals were provided ad libitum potable dextrane sulfate sodium solution (DSS) in order to reproduce an AIBD model and then individually exposed intraperitoneally to MSCs derived from BM (BM-MSCs), UCB (UCB-MSCs), ESCs (ESC-MSCs), or iPSCs (iPSC-MSCs). The parameters used to evaluate the cellular treatment efficacy were the animal survival prolongation and the histopathological-macroscopic picture of bowel sections. Although all categories of mesenchymal stem cells led to statistically significant survival prolongation compared to the control group, significant clinical and histopathological improvement was observed only in mice receiving BM-MSCs and UCB-MSCs. Our results demonstrated that the in vivo anti-inflammatory effect of ESC-MSCs and iPSC-MSCs was inferior to that of UCB-MSCs and BM-MSCs. Further investigation will clarify the potential of ESCs and iPSC-derived MSCs in AIBD treatment.
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Stem and Progenitor Cells in the Pathogenesis and Treatment of Digestive Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:125-157. [PMID: 31898785 DOI: 10.1007/978-3-030-31206-0_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The global epidemic of chronic degenerative diseases expands rapidly. The pathogenesis of these noncommunicable disorders revolves around innate immunity, microbiome, and stem cell alterations. Understanding the mechanisms behind stem cell biology and their regulatory pathways is a key to understanding the origin of human disease. Stem cells are involved in tissue and organ damage and regeneration. The evidence is mounting that not only eukaryotic cells but also gut microbiota may release extracellular microvesicles that are absorbed from the gut into the portal and systemic circulation. Linking the fields of stem cells, innate immunity and microbiome research opens up new avenues to develop novel diagnostic (e.g., biomarkers), therapeutic (e.g., microbiome modulation, stem cell-based medicines), and prognostic (personalized diets) tools. In this chapter, we present the short overview of various stem and progenitor cells of adult tissues circulating in peripheral blood and their role in the pathogenesis and treatment of digestive diseases. We also briefly discuss the role of host-stem cell-microbial interactions as a new frontier of research in gastroenterology.
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López-Beas J, Guadix JA, Clares B, Soriano-Ruiz JL, Zugaza JL, Gálvez-Martín P. An overview of international regulatory frameworks for mesenchymal stromal cell-based medicinal products: From laboratory to patient. Med Res Rev 2020; 40:1315-1334. [PMID: 32017179 DOI: 10.1002/med.21659] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022]
Abstract
Human mesenchymal stromal cells (hMSCs) are emerging as one of the most important cell types in advanced therapies and regenerative medicine due to their great therapeutic potential. The development of hMSC-based products focuses on the use of hMSCs as biological active substances, and they are considered medicinal products by the primary health agencies worldwide. Due to their regulatory status, the development of hMSC-based products is regulated by specific criteria that range from the design phase, nonclinical studies, clinical studies, to the final registration and approval. Patients should only be administered hMSC-based products within the framework of a clinical trial or after the product has obtained marketing authorization; in both cases, authorization by health authorities is usually required. Considering the above, this paper describes the current general regulatory requirements for hMSC-based products, by jurisdiction, to be implemented throughout their entire development process. These measures may provide support for researchers from both public and private entities and academia to optimize the development of these products and their subsequent marketing, thereby improving access to them by patients.
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Affiliation(s)
- Javier López-Beas
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Juan A Guadix
- Department of Animal Biology, Faculty of Sciences, Instituto Malagueño de Biomedicina (IBIMA), Campus de Teatinos s/n, University of Málaga, Málaga, Spain.,BIONAND, Centro Andaluz de Nanomedicina y Biotecnología (Junta de Andalucía, Universidad de Málaga), Málaga, Spain
| | - Beatriz Clares
- Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Jose L Soriano-Ruiz
- Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - José L Zugaza
- Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Patricia Gálvez-Martín
- Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Granada, Granada, Spain.,R&D Human Health, Bioibérica S.A.U., Barcelona, Spain
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Pan J, Lee YC, Lee HHC, Sung TC, Jen SH, Ban LK, Su HY, Chen DC, Hsu ST, Higuchi A, Chen H. Culture and differentiation of purified human adipose-derived stem cells by membrane filtration via nylon mesh filters. J Mater Chem B 2020; 8:5204-5214. [PMID: 32490480 DOI: 10.1039/d0tb00947d] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Human adipose derived stem cells purified by the membrane migration method through filter membranes coated with vitronectin showed high osteogenic differentiation.
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