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.

Keywords: Crohn’s disease; adipose-derived stem cells; allogenic stem cells; mesenchymal stem cells; perianal fistula.

Figure 1

Method for isolating adipose-derived stem cells (ADSC). The adipose tissue is minced with fine scissors or a scalpel, then washed, treated with collagenase and centrifuged. The resulting pellet (serum vascular fraction of hematopoietic, endothelial, vascular smooth muscle, fibroblastic and immature cells, AND ADSCs) is then resuspended in a complete medium before seeding in a culture plate and cultured in a specific medium that facilitates ADSC selection.

Figure 2

Main properties of adipose-derived stem cells (ADSC). (The secretome mainly contains interleukins, growth factors, indoleamine 2,3-dioxygenase, prostaglandin E2, NO, Lipoxin A4, Neurotrophin-3, etc.; the extracellular vesicles carry membrane and cytosolic proteins, transcription factors, DNA, mRNA, rRNA, miRNA and key molecules of various transduction signals …).

Figure 3

Mechanisms involved in adipose-derived stem cells (ADSCs)-associated beneficial effects in the inflamed gut.

Figure 4

Schematic representation of anoperineal fistulas in Crohn’s disease and of adipose-derived stem cell injections. The different types of fistulas are drawn in red. According to Park’s classification: 1: superficial; 2: inter-sphincteric; 3: trans-sphincter; 4: supra-sphincteric; 5: extra-sphincteric. According to the American Gastroenterological Association: simple fistulas = 1 + 2; complex fistulas = 3 + 4 + 5. In blue, different ADSC routes that are generally applied in refractory complex fistulas: 1: via the internal orifice of the fistula; 2: via the external orifice of the fistula; 3: in the peri-fistula space.

Figure 5

Algorithm for the management of perianal suppuration and complex fistula in Crohn’s disease including the place of stem cell therapy (*: ciprofloxacin and/or metronidazole).