Experts Corner: Mesenchymal Stem Cell Therapy for Chron’s Disease

Kenneth Pettine

Published by: Kenneth Pettine, M.D. (Retired)
Credit: https://www.kennethpettine.com
Secondary Credit Kenneth Pettine on Health Grades

Crohn’s disease is an inflammatory bowel disease (IBD). This condition results in inflammation of the lining of the digestive tract. This often leads to severe abdominal pain, diarrhea, fatigue, weight loss, and malnutrition. There is no cure for Crohn’s disease. Various medications can reduce its symptoms and possibly bring about temporary remission. Symptoms of Crohn’s disease can range from mild to severe. Symptoms can appear suddenly and require hospitalization due to the debilitating diarrhea and associated weight loss. The exact cause of Crohn’s disease remains unknown, but most experts believe it to be an autoimmune disorder. There is also a hereditary component. Patients with Crohn’s disease have a higher risk of developing colon cancer [1, 2, 3, 4].

Patients with Crohn’s disease often undergo colonoscopy, flexible sigmoidoscopy, CT scans, MRI scans, capsule endoscopy, double-balloon endoscopy and small bowel imaging to completely evaluate the digestive tract. Various anti-inflammatory drugs are used in an attempt to control the symptoms of Crohn’s disease. These can include oral 5-aminosalicylates, corticosteroids, and immune system-suppressing drugs such as lmuran, Purinethol, Remicade, Humira, Cimzia. These latter three drugs work by neutralizing an immune system protein known as tumor necrosis factor (TNF). Other drugs used to treat the symptoms of Crohn’s disease include methotrexate, which is a cancer drug, and various cyclosporins including Gengraf, Neoral, Sandimmune, Astagraf XL, and Hecoria. Cyclosporins have the potential of serious side effects including kidney and liver damage, seizures and fatal infections. Tysabri and Entyvio are drugs that work by stopping certain immune cell molecules (integran) from binding to other cells in your intestinal lining. The patients are also often treated with various antibiotics including Flagyl and ciprofloxacin. Various anti-diarrheal medications, pain relievers, iron supplements, vitamin B- 12 shots, and the use of calcium and vitamin D supplements can sometimes help Crohn’s disease. Surgery to remove damaged areas of the intestines can be temporarily helpful. Certain foods are recommended to be avoided such as dairy products and high fat containing foods. Other treatments include methods to reduce stress such as exercise, biofeedback, relaxation and breathing exercises. Various herbal and nutritional supplements can be taken. Probiotics and fish oil have not been found in studies to be helpful [9, 10, 11, 15, 16, 17, 18, 19, 20, 21).

I performed a literature review at the beginning of 2014 and was able to locate over 2, 000 peer-reviewed published papers concerning mesenchymal stem cells (MSC) in just the last three years. The MSC is by far the most studied adult stem cell in the body. The main focus of all this research has been on MSC’s ability to influence biological function through its trophic mechanisms, including the secretion of cytokines which might serve both paracrine (cells communicating with adjacent cells) and endocrine (cells communicating long distances through the body) functions [24 – 27]. This shift away from just using MSCs in orthopedics and spine is the result of scientific observations that MSC therapy results in reduction of inflammation and apoptosis (cell death) in numerous disease models. These positive systemic effects from the MSCs occurred before they differentiate into osteoblasts, chondroblasts, or fibroblasts. Thus, it has been discovered the MSC exerts these properties as a stem cell. This realization also resulted in a paradigm shift away from local injection of the MSCs into damaged tissue to systemic administration intravenously which is less invasive and more convenient to the patient.

When a stem cell clinic infuses bone marrow concentrate into an IV, this can range in volume from a few millimeters up to 20 ml of bone marrow concentrate. This material is put through a filter (Hemo-Nate ® Syringe Infusion Set) which removes the cell aggregates and particulates (18J.Lm or larger) prior to the slow infusion of the bone marrow concentrate. The mesenchymal stem cells travel through your venous system and the first filter they encounter is your lungs7 10. The MSCs trapped in pulmonary tissue eventually travel through capillaries into your arterial system and then travel throughout the body. Despite the MSCs temporary location in the pulmonary capillaries, numerous animal studies and some clinical trials have reported favorable outcomes following systemic infusion of MSCs. In a seminal paper by Lee, et al, a paracrine (cell signaling) factor was found to be released by MSCs in the pulmonary capillary bed. This factor promotes tissue regeneration through a systemic effect, similar to the action of a conventionally administered drug 4.

I would encourage you to read a recent paper published by Glen, et al, in the World Journal of StemCells11. The title of the article is Mesenchymal Stem Cells: emerging mechanisms of immunomodulation and therapy.” The following is a direct quote, “Currently, much research centers on the immunomodulatory aspects of MSCs, especially in reducing inflammation and suppressing immune cell function. Emerging research suggests a multi-functional quality of MSC immunomodulation.” This review paper dissects MSC manipulation of immune responses, which result in either immunosuppression or immunostimulation. The discovery of the immunomodulatory functions of MSCs has ushered in a plethora of research studying autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. Katata, et al, recently published a review article titled, “Parkinson’s Disease and Mesenchymal Stem Cells: potential for cell-based therapy.” This paper focuses mainly on the potential of mesenchymal stem cell as a therapeutic biologic treatment in Parkinson’s disease. The following is a direct quote from this paper “MSCs are a great therapeutic cell source because they are easily accessible and can be given to patients without posing serious ethical or technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson’s disease.”

The shift from local administration of MSC based treatments to systemic, or body wide administration has greatly expanded the potential of this natural regenerative medicine approach to treating diseases. As more targeted treatments are developed in disease specific models, it is likely that MSC therapies could replace the litany of harsh, side-effect laden immunosuppressive drugs for autoimmune diseases. Current drugs/treatments for autoimmune conditions can cause side effects that may be worse than the disease itself. For example, long-term levodopa use in Parkinson’s disease, which loses efficacy over time, requires careful monitoring, and can cause significant motor dyskinesias or involuntary motions.

All this research as well as early experience in our clinics indicates that IV stem cells may help with a number of conditions. We have treated a small number of patients with Parkinson’s, Multiple Sclerosis, fibromyalgia, rheumatoid arthritis, and even elevated liver enzymes from alcohol use who are reporting favorable results with no adverse events. These cases were not part of a formal study, so no prospective data was collected. We are currently planning and implementing clinical studies to objectively assess the benefits of IV bone marrow concentrate infusion. The primary goal of this research is to provide patients with the most cutting edge treatments in both orthopedics and general medicine.

Mesenchymal stem cells (MSCs) are attracted by cytokines to areas of inflammation.When an MSC arrives in areas of bodily damage they have been shown to actively participate in tissue repair. MSCs have the ability to suppress immune responses and have repeatedly shown efficacy in treating various autoimmune disea ses. The proven ability of MSCs to regenerate damaged tissue combined with their capacity to regulate immune and inflammatory responses, gives a strong rationale for using MSCs as a new treatment option in diseases characterized by inflammation with severe tissue damage such as Crohn’s disease [12, 13, 14].

Several human studies have been either initiated or completed concerning the use of mesenchymal stem cells to treat Crohn’s disease. The largest randomized placebo controlled double-blind phase Ill human study is prochymal produced by osirus. Prochymal is bone marrow derived mesenchymal stem cells from a donor human. This is an FDA controlled study. I would strongly encourage you to read the three papers that have been generated from this study [6, 7, 8].

Dalal has published a well-written literature review of human studies utilizing mesenchymal stem cell for Crohn’s disease. In his conclusion, he states analysis of numerous papers in the literature had confirmed the safety of mesenchyma lstem cells in large numbers of patients. There is a shift in the treatment of Crohn’s disease towards cellular therapy. At this point, research has not indicated the best source of mesenchymal stem cell, the best administration route, or the quantity of cells to produce optimal
clinical results. Future studies are required. Clinical trials in the use of mesenchymal stem cell for
Crohn’s disease can be divided into the following categories. The MSCs are injected intravenously and come either from the patient or a donor, the mesenchymal stem cells are injected directly into the
fistulas of the affected intestines and are obtained either from the patient or a donor [5].

Molendijk, et. al. published a chapter concerning mesenchymal therapy for Crohn’s disease. The full paper is also included in our references. They conclude that in vitro (in the laboratory) and in vivo animal and human clinical data show a potential for MSCs as a new treatment modality for inflammatory bowel diseases including Crohn’s disease. Promising initial results have been published. Several clinical studies have demonstrated the clinical efficacy for Crohn’s disease, but the exact treatment dose, timing and frequency of administration, as well as the optimal source of MSCs are currently under investigation [23].

Beginning approximately one year ago, we began systemically infusing the MSCs intravenously (IV) to utilize the amazing functions of the MSC throughout your body. This is a quote from an NIH manuscript22. “Imagine a simple intravenous cell therapy that can restore function to damaged or diseased tissue, avoid host rejection and reduce inflammation throughout the body without the use of immunosuppressive drugs. Such a breakthrough would revolutionize medicine. Fortunately, pending regulatory approval, this approach might not be far off. Specifically, cell therapy utilizing adult MSCs, multipotent cells with the capacity to promote angiogenesis, differentiate to produce multiple types of connective tissue, and down-regulate an inflammatory process, is the focus of a multitude of clinical studies currently underway. MSCs are being explored to regenerate damaged tissue and treat inflammation resulting from: cardiovascular disease and myocardial infarction (MI), brain and spinal cord injuries, stroke, diabetes, cartilage and bone injury, Crohn’s disease, and graft versus host disease. In this article we highlight the recent paradigm shift which has occurred in therapeutic use of MSC based on their immunomodulatory properties as opposed to their ability to differentiate into osteoblasts, chrondoblasts, or fibroblasts22.”

The procedure to place mesenchymal stem cells into peripheral vein is as follows:

To start the procedure, an IV will be started, typically in an arm. Antibiotics are placed into the IV and a small dose of versed is given intravenously for relaxation. The patient is transported to the procedure room to lay on a table similar to a massage table. The patient is placed on their abdomen and additional medication is given consisting of more IV versed and fentanyl (narcotic). At this point, most people are asleep or extremely relaxed. The versed also causes the patient to experience retrograde amnesia. Once the patient is completely relaxed or asleep, the skin area around the posterior iliac wing (the hip) is sterilized with betadine and draped sterilely. The skin is anesthetized with buffered 1% xylocaine. Utilizing fluoroscopic control, a Jamshidi needle is placed into the patient’s posterior iliac wing. At this point, anywhere from 60 to 120 mL of bone marrow is carefully extracted. This entire procedure is performed with the patient asleep or highly relaxed.

Following this procedure, the patient is placed in a wheelchair and transported back to a comfortable lounge chair to sleep or remain highly relaxed for approximately one half hour. During this time the bone marrow aspirate is placed in a centrifuge for approximately 15 minutes. This separates the bone marrow aspirate into various cell layers with red blood cells being at the bottom of the tube and plasma at the top. A small layer in the middle contains all of the nucleated cells including the mesenchymal stem cells. This layer is extracted and placed through a Hemo-Nate® Syringe Infusion Set. This filter removes all of the aggregates and particulates that are 1811m (Micrometers) or larger. The mesenchymal stem cell layer is placed into your IV at a rate of approximately 1mL per minute. The mesenchymal stem cells then travel to the capillary bed of the patient’s lungs where they remain for a few hours and then travel throughout the body. The mesenchymal stem cells are attracted to areas of inflammation in the body. They also release various growth factors and communicate to other cells to modulate the immune system. The IV is removed and the patient is transported home with a driver. Usually, people feel discomfort in their hip for approximately 24 hours from the removal of bone marrow, and may feel relaxed or sleepy for several hours following the procedure.

Case Study:
The study patient was a 56-year old male who was diagnosed with Crohn’s disease in 2006. Since his diagnosis, the patient has suffered from symptoms such as nausea, cyclic vomiting, blood in stool, cramping, general abdominal pain, and headaches. To alleviate these symptoms, the patient at one point was taking mercaptopurine (30mg daily), methadone (40mg daily), and indicated post-treatment that they had been receiving infliximab therapy every 16 weeks. Prior to any stem cell treatment, the patient was driven or taken by ambulance to the emergency room every 2-3 months to treat the more intense symptoms. In December of 2014, the patient underwent intravenous mesenchymal stem cell therapy in order to find alternative relief. Six months after receiving the IV treatment, the patient indicated he had significant alleviation of his symptoms and had not been to the emergency room since. While he still sought infliximab therapy every 16 weeks following the stem cell procedure, the patient had reduced his methadone dosage to 10mg daily from 40mg daily and ceased taking mercaptopurine. After completing a general health survey six months post-treatment, the patient’s scores indicate his physical, emotional, and social health had all improved, as well as his pain threshold, day to day functioning, and other daily activities. The data acquired from this patient reveals he achieved significant relief from his Crohn’s disease symptoms through the IV stem cell treatment. He continues to show benefit two years later.

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