Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn’s Disease: Rationale, Clinical Results and Perspectives

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.

Mesenchymal Stem Cell-Derived Secretome: A Potential Therapeutic Option for Autoimmune and Immune-Mediated Inflammatory Diseases

“…The efficacy and safety of the MSC-secretome have also been demonstrated in animal studies. It is hypothesized that if MSCs are injected locally into the therapy-refractory fistulas of Crohn’s disease patients, the closure of fistulas is mainly due to the immunomodulatory activity of the secretome, instead of the MSCs per se [ 136 ].…”

Engineering the next generation of cell-based therapeutics

“…Despite their preclinical promise, most early efforts to translate MSC-based therapies lacked appropriate product quality controls owing to variability in cell isolation procedures, culture conditions and final expansion processes, with resulting product inconsistencies leading to numerous clinical failures 36 . The previously mentioned treatment for Crohn’s disease-associated fistulas, darvadstrocel, currently offered in the EU and Japan 2 , is one of a handful of commercialized MSC products. Another well-known product is remestemcel-L, which uses donor-derived, culture-expanded MSCs to treat GvHD 37 .…”

“…These include the successful treatment of lymphoid cancers using adoptive cell transfer of genetically reprogrammed T cells, resulting in FDA approval of tisagenlecleucel and axicabtagene ciloleucel in 2017 for the treatment of acute lymphoblastic leukaemia (ALL) and large B cell lymphoma (LBCL), respectively. Other recent successes have included approval of the use of patient-derived limbal stem cells to repair damaged corneal epithelia 1 , as well as adult stem cells to treat fistulas associated with Crohn’s disease 2 . These breakthroughs were built upon decades of basic research, and their successes as well as that of other vanguard therapies have had the effect of stimulating enormous cross-disciplinary interest from many previously disconnected basic biomedical research and engineering fields.…”

Therapeutic Strategy of Mesenchymal-Stem-Cell-Derived Extracellular Vesicles as Regenerative Medicine

“…More than 500 clinical research on MSC is underway in the world for various target diseases, including rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, myocardial infarction, Parkinson’s disease, spinal cord injury, osteoarthritis, and graft-versus-host disease (GVHD) [ 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 ]. MSCs other than those derived from bone marrow are also being clinically applied.…”