Stem Cell Therapy as a Treatment for Inflammatory Bowel Disease
An introduction to stem cell therapy (SCT), a promising new treatment which offers new possibilities for relief from gastrointestinal disorders including ulcerative colitis, Crohn’s disease and IBS.
Does stem cell therapy exist for IBD?
Approximately 33% of patients with Crohn’s disease do not respond to anti-TNF-α therapy.123 Also, nearly 30% of responders usually lose their response to current medical regimen.4
Patients who become refractory to medical treatment require surgery. Based on recent research, up to 60% of patients with Crohn’s disease will require a bowel resection, and 15% with ulcerative colitis will undergo a colectomy.
There is a clear need for improvement of medical treatment in order to avoid surgical intervention. That is why stem cell therapy is the last resort of conservative treatment before surgical operations.
What are stem cells?
There are two types of stems cells that concern us, embryonic and adult. Embryonic stem cells are the kind you frequently hear about in the news. They are some of the very first cells that develop in a human embryo, and over 200 cell types in our bodies are developed from them. This is why they are called “stem” cells, because at one early point in our development, we all originate with and are derived from our stem cells.
Adult stem cells are more specialized than embryonic. They are only capable of forming cells in the region of the body they originate, and vary depending on that location. They remain waiting and unassigned until the body needs extra cells, then configure themselves in different ways and adapt their function, working as needed to promote health and repair damage, but only in the particular area where they were formed.
Stem cells are your body’s equivalent of hosting a jack-of-all-trades handyman in your home, who can make repairs, cook dinner and so on, but may also burn your house down or just lay on the sofa doing nothing.
Most importantly for us, can this strange handyman fix your IBD?
What are the types of stem cells?
There are three major types of stem cells:
- Adult stem cells
- Also called tissue-specific stem cells, these are specialized stem cells for specific tissue and located within their tissue of origin. They are characterized by the ability of self-renewal and also differentiation into only specific tissue cell type. Adult tissues containing stem cells are skin, muscle, intestine, and bone marrow.
They can only differentiate into the mature cell type of the organ within which they reside.
- Embryonic stem (ES) cells
- Derived from the inner cell mass of the developing embryo during the blastocyst stage. They are pluripotent and can theoretically give rise to any cell type if exposed to the proper stimuli. Adult stem cells only differentiate into the specific tissue from which they were harvested.
It is very hard to differentiate embryonic stem cells into a particular cell type. They may transform into cancerous (malignant) tissue or – after transplantation – an immunological mismatch may occur, killing all cells and canceling their effect. But those dangerous complications are only secondary reasons embryonic stem cells are avoided. The main reason is because the cells are taken from a potentially viable embryo, which raises serious ethical concerns.
- Induced pluripotent stem (iPS) cells
- Pluripotent cells, like embryonic stem cells. Today, there are no clinical trials using iPS cells, so there is no need for further review here.
For IBD: mesenchymal stem cells
The only type of stem cells that are used for the treatment of inflammatory bowel diseases are mesenchymal stem cells.
Types of adult stem cells
Within the category of adult stem cells, there are two types:
- Hematopoietic stem cells
- Can be used after the destruction of bone marrow to repopulate it in patients with hematologic disorders or malignancies. These cells are found most abundantly in the bone marrow, but can also be harvested at birth from umbilical cord blood.
- Mesenchymal stem cells
- Isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available.
They can differentiate into different cell types: osteoblasts (bone tissue), chondrocytes (joint tissue), and adipocytes (fat tissue).567
Note that the only type of stem cells that are used for the treatment of inflammatory bowel diseases are mesenchymal stem cells.
How do mesenchymal stem cells treat inflammatory bowel disease?
One of the mechanisms through which mesenchymal stem cells may be used for the treatment of inflammatory bowel disease is via the promotion of regulatory T-cell (Treg) formation. This type of cell is deficient in patients with inflammatory bowel disease.8
Mesenchymal stem cells promote the generation of Tregs directly by the constitutive production of TGF-β1 and indirectly by influencing the differentiation of monocytes toward CCL18-producing type 2 macrophages.
How do stem cells find the factor which influences the progression of inflammatory bowel disease?
One problem is that the targeted delivery of stem cells is needed for inflammatory bowel diseases, since they involve specific regions of the intestine. For example, Crohn’s disease affects any area from the mouth to the anus, but often presents with skip lesions (a patchy kind of wound, which “skips” areas, leaving some areas unharmed), or limited regions of the bowel are affected, whereas UC is characteristically seen as continuous inflammation from rectum to cecum.
It was found that stem cells facilitate epithelial repair in inflammatory bowel disease upon systemic delivery.9 Researchers induced moderate to severe ulcerative colitis in mice by dextran sulfate sodium treatment. Once colitis was present, two million human CD34 stem cells were infused twice via the tail vein. The group found that the stem cells significantly reduced the colitis severity score in moderate (P=0.0003) and severe (P<0.0001) ulcerative colitis after 35 days.
More importantly, the group also found that the stem cells homed in on the damaged digestive tract tissue — on histology, stem cells were detected predominantly in the submucosa of the damaged colonic epithelium following the killing. This secondary discovery that the stem cells selectively traveled and engrafted at sites of colonic inflammation and injury has important implications for the systemic use of stem cells to treat inflammatory bowel disease.
Thus, it was concluded that stem cells specifically migrate to areas of damaged tissue, which is significant in patients with Crohn’s disease and ulcerative colitis who have specific segments of bowel affected.10
Where are stem cells taken from?
Stem cells can be harvested and transplanted into the patient via two main routes:
- Allogeneic (donor-derived) stem cells are transplantations of stem cells from a healthy donor – in short, from another person.
- Autologous (self-derived) stem cells are derived from the patient’s body, that is, from you.
How are stem cells delivered into the body?
There are several routes of delivery of stem cells:
- Intravenous (IV)
- The safest and simplest method for delivering the stem cells throughout the body. Anesthesia is not required but light anesthesia can be administered if necessary.
- Intramuscular (IM)
- Stem cells are injected directly into the muscle.
- Intra-articular (IA)
- Stem cells are injected directly into the affected joint by a licensed physician. This method is commonly used for arthritis.
- Intrathecal (lumbar puncture, aka, spinal tap)
- Intrathecal administration is ideal for neurological conditions because the stem cells are injected directly into the spinal fluid via the lumbar puncture past the blood-brain barrier. This enables them to reach the spinal cord and brain.
The most likely route for stem cell therapy for inflammatory bowel disease is intravenous or intramuscular delivery.
How many infusions of stem cells are needed?
It depends on the clinic and the severity of the disease. For example, at the Stem Cell Institute, patients typically receive between 3 and 16 stem cell applications during the course of an entire treatment protocol.11
Are there any risks connected with stem cells therapy?
Yes, and there are a lot of potential risk factors.
Overview of risk factors and risks associated with stem cell-based therapy:
| Risk factors or hazards | Identified risks | |
|---|---|---|
| Intrinsic factors |
|
|
| Cell characteristics |
|
|
| Extrinsic factors Manufacturing and handling |
|
|
| Clinical characteristics |
|
|
Clinical trials on stem cell therapy for Crohn’s and ulcerative colitis
| Study name | Researchers | Type | Date | Disease | Summary | Conclusion |
|---|---|---|---|---|---|---|
| Clinical efficacy and safety of stem cells in refractory Crohn's disease: A systematic review | Ye, Lei, Xiaowei Wu, Na Yu, Jingxin Pan, Lianming Liao, and Fangyu Wang | Meta-analysis | March 2016 | Crohn's disease | It seems stem cells can reduce Crohn's Disease Activity Index (CDAI) and help alleviate CD symptoms. Moreover, the incidence of serious adverse events caused by stem cell transplantation was very low (1.75%, 7/400). | Positive |
| Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis | Dave M1, Mehta K, Luther J, Baruah A, Dietz AB, Faubion WA Jr. | Meta-analysis | November 2015 | Crohn’s disease | MSCs are emerging as an alternative treatment for refractory IBD. Although, MSCs appear safe and potentially effective in initial studies, more studies in preclinical animal models and human studies that incorporate randomized controlled design are needed. | Inconclusive |
| Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn's disease | Qiu Y1, Li MY1, Feng T1, Feng R1, Mao R1, Chen BL1, He Y1, Zeng ZR1, Zhang SH2, Chen MH3 | Meta-analysis | January 2017 | Crohn's disease | SCT seems potentially effective and may serve as an alternative treatment for refractory active CD. Toxicity will remain the most significant barrier to systemic SCT in patients with CD. | Inconclusive |
| Efficacy and safety of autologous hematopoietic stem cell therapy for refractory Crohn's disease A systematic review and meta-analysis | Xiao Qiu, MD, Jue-Rong Feng, MD, Li-Ping Chen, MD, Shi Liu, MD, Meng Zhang, MD, Zhou Zhou, MM, Jing Liu, MD, and Qiu Zhao, MD | Meta-analysis | June 2017 | Crohn's disease | Autologous HSCT could be a complicated treatment with relatively high mortality and significantly high efficacy for refractory CD, which should be used with caution. However, more RCTs of larger samples using refined and standardized protocols and longer period of follow-up time are needed to further assess the outcomes of autologous HSCT therapy. | Inconclusive |
| Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis | Maneesh Dave, MBBS, MPH,* Kathan Mehta, MBBS, MPH, Jay Luther, MD, Anushka Baruah, MBBS, Allan B. Dietz, PhD, and William A. Faubion, Jr, MD | Meta-analysis | July 2015 | Crohn's disease and ulcerative colitis | Taken together, these studies suggest a promising role for stem cell therapy in IBD although the substantial challenges, such as cost and inadequate/incomplete characterization of effect, limit their current use in clinical practice. | Inconclusive |
| Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial | Dr James O Lindsay, PhD, Prof Mathieu Allez, PhD, Miranda Clark, BSc, Myriam Labopin, MD, Elenor Ricart, PhD, Prof Gerhard Rogler, PhD, Montserrat Rovira, MD, Prof Jack Satsangi, DPhil, Prof Dominique Farge, PhD, Prof Christopher J Hawkey, FMedSci | Clinical trial | April 2017 | Crohn's disease | When assessed using endpoints traditional for clinical trials of conventional therapy in Crohn's disease, HSCT resulted in clinical and endoscopic benefit, although it was associated with a high burden of adverse events. The prognostic factors identified could allow the therapy to be targeted to patients most likely to benefit and not experience serious adverse events. | Inconclusive |
| Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease | Panés, García-Olmo, Van Assche, Colombel, Reinisch, Baumgart, Dignass, Nachury, Ferrante, Kazemi-Shirazi, Grimaud, de la Portilla, Goldin, Richard, Diez, Tagarro, Leselbaum, Danese | Clinical trial | April 2018 | Complex Perianal Fistulas in Patients With Crohn's Disease | In a phase 3 trial of patients with Crohn's disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. | Positive |
No matter the results of meta-analyses – which reveal a positive effect of stem cell therapy on inflammatory bowel disease – all studies included here have a high risk of performance bias, detection bias, attrition bias, and reporting bias.
Based on the results of clinical trials – 12 clinical trials were completed, and only one has published results. Based on the available results there were no significant differences in all primary – Endoscopic Score, Rectal Bleeding at Week 4 and 8, Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) – and secondary outcomes. This clinical trial was the biggest one and the change of bias is minimal. This means that stem cell therapy most likely has low therapeutic effect.
Stem cell therapy for IBD
Using stem cell therapy for inflammatory bowel disease is a risky and expensive procedure. It should only be attempted only as your last resort for treatment.
How much does stem cell therapy for Crohn’s cost?
It usually depends on the clinic, their services, and protocol length. The typical fee for stem cell therapy is about $15,000 to $30,000 or more.
Does insurance cover stem cell therapy?
Unfortunately, insurance companies do not normally cover adult stem cell therapy.
Where can I get stem cell therapy for severe ulcerative colitis or Crohn’s?
Stem cell therapy is not widely available, but you can receive the treatment in a few countries.
- Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541-9. 10.1016/S0140-6736(02)08512-4 [PubMed] [CrossRef]
- Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52-65. 10.1053/j.gastro.2006.11.041 [PubMed] [CrossRef]
- Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228-38. 10.1056/NEJMoa067594 [PubMed] [CrossRef]
- Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol 2011;106:685-98. 10.1038/ajg.2011.103 [PubMed] [CrossRef]
- Okamoto R, Watanabe M. Investigating cell therapy for inflammatory bowel disease. Expert Opin Biol Ther 2016;16:1015-23. 10.1080/14712598.2016.1177019 [PubMed] [CrossRef]
- Bieback K, Netsch P. Isolation, culture, and characterization of human umbilical cord blood-derived mesenchymal stromal cells. Methods Mol Biol 2016;1416:245-58. 10.1007/978-1-4939-3584-0_14 [PubMed [CrossRef]
- Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. 10.1126/science.284.5411.143 [PubMed] [CrossRef]
- Mayne CG, Williams CB. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis 2013; 19: 1772–1788. [PMC free article] [PubMed
- Khalil PN, Weiler V, Nelson PJ et al. Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease. Gastroenterology 2007; 132: 944–954. [PubMed]
- See Khalil.
- Masoumeh Mousavinejad, E. (2018). Current Biosafety Considerations in StemCell Therapy. [online] PubMed Central (PMC). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988427/ [Accessed 29 Dec. 2018].
Sergii Vasyliuk
Site link
In 2014, Dr. Vasyliuk graduated from the Ivano-Frankivsk medical University in Ukraine. He received his diploma with honors for excellent marks and for the active role in the research project ‘Non-compaction cardiomyopathy’. He is the author of 7 scientific medical articles. In 2017, he successfully completed his residency in ‘General Surgery’ and continued his studies in the field of Vascular Surgery. In the same year, he passed his USMLE exams and received an ECFMG certificate in the USA. In 2018, he became a Vascular surgeon. Currently, he works in the Ivano-Frankivsk regional hospital and gives consultation to gestating women with...
In 2014, Dr. Vasyliuk graduated from the Ivano-Frankivsk medical University in Ukraine.
He received his diploma with honors for excellent marks and for the active role in the research project ‘Non-compaction cardiomyopathy’. He is the author of 7 scientific medical articles.
In 2017, he successfully completed his residency in ‘General Surgery’ and continued his studies in the field of Vascular Surgery. In the same year, he passed his USMLE exams and received an ECFMG certificate in the USA.
In 2018, he became a Vascular surgeon. Currently, he works in the Ivano-Frankivsk regional hospital and gives consultation to gestating women with varices in a maternity hospital as a vascular surgeon.
Comments