Mesenchymal stromal cell therapy for Crohn's disease : from perianal fistulizing disease to experimental colitis

A frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous discharge from the fistula causing skin irritation. Nowadays, a wide range of medical and surgical therapies for perianal fistulizing CD is available. However, achieving complete fistula healing is often a long process preceded by multiple relapses during the treatment. Currently, mesenchymal stromal cells (MSCs) have gained much interest as a potential therapeutic option for inflammatory disorders, including fistulizing CD, because they possess immunosuppressive and tissue regenerative properties. We performed a clinical trial evaluating MSCs as a treatment for perianal fistulas. Local administration of MSCs additional to a standardized surgical treatment was safe and feasible and resulted in a higher percentage of healed fistulas compared to placebo. In addition, several experimental studies were performed to unravel the mechanism of action of MSCs. The role of the time of MSC administration, disease severity, prestimulation of MSCs with inflammatory cytokines, migration of MSCs and the formation of spheroid-like structures are described in this thesis.Grant: DigestScience Foundation Sponsoring drukkosten: AbbVie B.V., ABN AMRO, BD Biosciences, ChipSoft B.V., Dr. Falk Pharma Benelux B.V., EuroTec B.V., Greiner Bio-One B.V., Dutch Society of Gastroenterology (NVGE), Olympus Nederland B.V., Section Experimental Gastroenterology (SEG) of the Dutch Society of Gastroenterology (NVGE), Stopler Instrumenten & Apparaten B.V., Takeda Nederland B.V.UBL - phd migration 201

Lymphoproliferative disease in the rectum 4 years after local mesenchymal stromal cell therapy for refractory perianal Crohn's fistulas:a case report

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The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC

Background: Constitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the β-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the β-catenin paradox. Methods: We analysed the expression patterns of SMAD4, p53 and β-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to s

Mesenchymal stromal cell therapy for Crohn's disease : from perianal fistulizing disease to experimental colitis

A frequent manifestation of Crohn's disease (CD) is the formation of perianal fistulas which can greatly affect patient's quality of life due to continuous pain, abscess formation and malodourous discharge from the fistula causing skin irritation. Nowadays, a wide range of medical and surgical therapies for perianal fistulizing CD is available. However, achieving complete fistula healing is often a long process preceded by multiple relapses during the treatment. Currently, mesenchymal stromal cells (MSCs) have gained much interest as a potential therapeutic option for inflammatory disorders, including fistulizing CD, because they possess immunosuppressive and tissue regenerative properties. We performed a clinical trial evaluating MSCs as a treatment for perianal fistulas. Local administration of MSCs additional to a standardized surgical treatment was safe and feasible and resulted in a higher percentage of healed fistulas compared to placebo. In addition, several experimental studies were performed to unravel the mechanism of action of MSCs. The role of the time of MSC administration, disease severity, prestimulation of MSCs with inflammatory cytokines, migration of MSCs and the formation of spheroid-like structures are described in this thesis.</p

Immunomodulatory Effects of Mesenchymal Stromal Cells in Crohn’s Disease

The ability of mesenchymal stromal cells (MSCs) to suppress immune responses combined with their potential to actively participate in tissue repair provides a strong rationale for the use of MSCs as a new treatment option in diseases characterized by inflammation and severe tissue damage, such as Crohn’s disease (CD) and perianal fistulas. Multiple studies have shown that MSCs suppress a range of immune cells, such as dendritic cells (DC), naïve and effector T cells, and natural killer (NK) cells. Recently published papers attribute the immunosuppressive capacity of MSCs to soluble factors produced by MSCs, such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO). Promising results are obtained from phase I and II clinical trials with autologous and allogeneic MSCs as treatment for refractory CD and perianal fistulas; however the question remains: what are the molecular mechanisms underlying the immunomodulating properties of MSCs? This paper highlights the present knowledge on the immunosuppressive effects of MSCs and its complexity in relation to CD and perianal fistulas

Immunomodulatory effects of mesenchymal stromal cells in Crohn's disease.

The ability of mesenchymal stromal cells (MSCs) to suppress immune responses combined with their potential to actively participate in tissue repair provides a strong rationale for the use of MSCs as a new treatment option in diseases characterized by inflammation and severe tissue damage, such as Crohn's disease (CD) and perianal fistulas. Multiple studies have shown that MSCs suppress a range of immune cells, such as dendritic cells (DC), naïve and effector T cells, and natural killer (NK) cells. Recently published papers attribute the immunosuppressive capacity of MSCs to soluble factors produced by MSCs, such as prostaglandin E2 (PGE(2)), inducible nitric oxide synthase (iNOS), and indoleamine 2,3-dioxygenase (IDO). Promising results are obtained from phase I and II clinical trials with autologous and allogeneic MSCs as treatment for refractory CD and perianal fistulas; however the question remains: what are the molecular mechanisms underlying the immunomodulating properties of MSCs? This paper highlights the present knowledge on the immunosuppressive effects of MSCs and its complexity in relation to CD and perianal fistulas

Local but not systemic administration of mesenchymal stromal cells ameliorates fibrogenesis in regenerating livers

Chronic liver injury leads to the accumulation of myofibroblasts resulting in increased collagen deposition and hepatic fibrogenesis. Treatments specifically targeting fibrogenesis are not yet available. Mesenchymal stromal cells (MSCs) are fibroblast-like stromal (stem) cells, which stimulate tissue regeneration and modulate immune responses. In the present study we assessed whether liver fibrosis and cirrhosis can be reversed by treatment with MSCs or fibroblasts concomitant to partial hepatectomy (pHx)-induced liver regeneration. After carbon tetrachloride-induced fibrosis and cirrhosis, mice underwent a pHx and received either systemically or locally MSCs in one of the two remaining fibrotic/cirrhotic liver lobes. Eight days after treatment, liver fibrogenesis was evaluated by Sirius-red staining for collagen deposition. A significant reduction of collagen content in the locally treated lobes of the regenerated fibrotic and cirrhotic livers was observed in mice that received high dose MSCs. In the non-MSC-treated counterpart liver lobes no changes in collagen deposition were observed. Local fibroblast administration or intravenous administration of MSCs did not ameliorate fibrosis. To conclude, local administration of MSCs after pHx, in contrast to fibroblasts, results in a dose-dependent on-site reduction of collagen deposition in mouse models for liver fibrosis and cirrhosis.status: publishe

Mesenchymal stromal cell function is not affected by drugs used in the treatment of inflammatory bowel disease

Mesenchymal stromal cells (MSC) have both multilineage differentiation capacity and immunosuppressive properties. Promising results with MSC administration have been obtained in experimental colitis. Clinical application of MSC for the treatment of inflammatory bowel disease (IBD) is currently under investigation in phase I-III trials in patients with past or concurrent immunomodulating therapy. However, little is known about MSC interactions with these immunosuppressive drugs. To address this issue we studied the combined effect of MSC and IBD drugs in in vitro functionality assays. The effects of azathioprine, methotrexate, 6-mercaptopurine and anti-tumor necrosis factor (TNF)-α on MSC phenotype, survival, differentiation capacity and immunosuppressive capacity were studied. MSC exposed to physiologically relevant concentrations of IBD drugs displayed a normal morphology and fulfilled phenotypic and functional criteria for MSC. Differentiation into adipocyte and osteocyte lineages was not affected and cells exhibited normal survival after exposure to the various drugs. MSC suppression of peripheral blood mononuclear cell (PBMC) proliferation in vitro was not hampered by IBD drugs. In fact, in the presence of 6-mercaptopurine and anti-TNF-α antibodies, the inhibitory effect of this drug alone was enhanced, suggesting an additive effect of pharmacotherapy and MSC treatment. This study demonstrates that, in vitro, MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. These findings are important for the potential clinical use of MSC in combination with immunomodulating drugs and anti-TNF-α therap