Pregnancy and Delivery Unaffected in Women Patients With Crohn’s Disease Who Were Treated With Fat-Based Stem Cells


Fat is a readily accessible source of mesenchymal stem cells (MSCs). When fat is extracted by liposuction, the result is a so-called stromal vascular fraction (SVF) that contains a mishmash of mast cells (important in allergies), blood vessel-making cells, blood vessel-associated cells, fibroblasts, and MSCs. These adipose-derived stem cells (ASCs) as they are called, can be relatively easily prepared once the SVF is digested by enzymes, and centrifuges. The living adult MSCs are then rather easily identified because they adhere to plastic tissue culture plates.

Fat-based MSCs have been used in clinical studies to help heal patients with Crohn’s disease who have “fistulas.”  For a picture of a fistula, see here.  Crohn’s disease (CD) is one of a group of gastrointestinal diseases known as IBDs or inflammatory bowel diseases. CD features inflammation of any part of the GI tract, and this inflammation can affect multiple layers of the GI tract. Fistulas form when a hole is eroded through the GI tract and into another organ system. For example, in women, the rectum and erode and form an opening in the vagina. Alternatively, an opening can appear in some place other than the anus. Because of the repeated irritation and extensive inflammation of these lesions, they tend to not heal.

Beginning in 2003, Damián García-Olmo and his team at the Jiménez Diaz Foundation University Hospital in Madrid, Spain have tested the efficacy of fat-based stem cells in treating patients with CD-based fistulas.  The results have been encouraging and highly positive, since ASCs promote healing of the fistulas and decrease recovery time (see de la Portilla F, et al. (2013) Int J Colorectal Dis 28:313–323; García-Olmo D, et al. (2003) Int J Colorectal Dis 18:451–454; García-Olmo D, et al. (2005) Dis Colon Rectum 48:1416–1423; Garcia-Olmo D, et al. (2009) Dis Colon Rectum 52:79–86).

Recently, Garcia-Olmo and his colleagues examined data from several their patients who went on to become pregnant after their treatment with fat-based stem cells and even given birth. This study, which was published in the June 2015 edition of Stem Cells Translational Medicine, examined six patients from these previous clinical trials who were successfully treated with fat-based stem cells, had satisfactory resolution and healing of their lesions, and then went on to become pregnant and give birth.

Of the five women examined in this study, one was treated for rectovaginal and perinatal fistulas, two for rectovaginal fistulas only, and two others for perianal fistulas only. All women received 2 doses of 20 million and 40 million stem cells at three-four-month intervals. One patient, however, received 2 doses of 6.6 million and 20 million stem cells nine months apart.

The fertility of these women and their pregnancies were unaffected by their previous cell therapies. There were no signs of treatment-related malformations in the babies they delivered, and their bodies did not show any identifiable signs of structural abnormalities as a result of the stem cell treatments. It must be said, that all four women who delivered healthy babies (one of them even had twins) elected for Caesarian sections. The fifth woman, unfortunately, miscarried twice, both times during the first trimester.

However, even though this represents a small data set, this study does strongly suggest that injection of a patient’s own fat-based stem cells does not negatively affect a woman’s ability to conceive, the course of her pregnancy, or the health of her baby.

A Patient’s Own Stem Cells Treats Their Crohn’s Disease


Stem cells isolated from the fat of patients with Crohn’s disease, an inflammatory disease of the bowel, relieved them from fistulas, which are a common, and potentially dangerous side effect of the disease. This is according to the results of a phase 2 clinical trial published in the latest issue of STEM CELLS Translational Medicine (SCTM).

Patients with Crohn’s disease suffer from a painful, chronic disease in which the body’s immune system attacks its own gastrointestinal tract. In Crohn’s patients, inflammation within the bowel can sometimes extend completely through the intestinal wall and create a what is known as a “fistula.”. Fistulas are abnormal connections between the intestine and another organ or even the skin. If left untreated, a fistula can become infected and form an abscess that can be life threatening.

Chang Sik Yu, M.D., Ph.D., of the Asan Medical Center in Seoul, Korea, who is a senior author of the SCTM paper, describes the results of a clinical trial that was conducted in collaboration with four other hospitals in South Korea. According to Dr. Yu: “Crohn’s fistula is one of the most distressing diseases as it decreases patient’s quality of life and frequently recurs. It has been reported to occur in up to 38 percent of Crohn’s patients and over the course of the disease, 10 to 18 percent of them must undergo a proctectomy, which is a surgical procedure to remove the rectum.”

Overall, the treatments currently available for Crohn’s fistula remain unsatisfactory because they fail to achieve complete closure, lower recurrence of the fistulas and do not limit adverse effects, Dr. Yu said. Given the challenges and unmet medical needs in Crohn’s fistula, attention has turned to stem cell therapy as a possible treatment.

Several studies, including those undertaken by Dr. Yu’s team, have shown that mesenchymal stem cells (MSCs) do indeed improve Crohn’s disease and Crohn’s fistula. Their phase II trial enrolled 43 patients for a term of one year, over the period from January 2010 to August 2012. These patients received injections of their own fat-based MSCs, and 82 percent of them experienced complete closure of fistula eight weeks after the final ASC injection. 75 percent of the trial participants remained fistula-free two years later.

“It strongly demonstrated MSCs derived from ASCs are a safe and useful therapeutic tool for the treatment of Crohn’s fistula,” Dr. Yu said.

The latest study was intended to evaluate the long-term outcome by following 41 of the original 43 patients for yet another year. Dr. Yu reported, “Our long-term follow-up found that one or two doses of autologous ASC therapy achieved complete closure of the fistulas in 75 percent of the patients at 24 months, and sustainable safety and efficacy of initial response in 83 percent. No adverse events related to ASC administration were observed. Furthermore, complete closure after initial treatment was well sustained.”

“These results strongly suggest that autologous ASCs may be a novel treatment option for Crohn’s fistulae,” he said.

“Stem cells derived from fat tissue are known to regulate the immune response, which may explain these successful long-term results treating Crohn’s fistulae with a high risk of recurrence,” said Anthony Atala, M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

Treating Crohn’s Disease Fistulas with Fat Stem Cells


All of us have probably heard of Crohn’s disease or have probably known someone with Crohn’s disease. While the severity of this disease varies from patient to patient, some people with Crohn’s disease simply cannot get a break.

Crohn’s disease is one of a group of diseases known as IBDs or “Inflammatory Bowel Diseases.” IBDs include Crohn;s disease, which can affect either the small or large intestine and rarely the esophagus and mouth, ulcerative colitis, which is restricted to the large intestine, and other rarer types of IBDs known that include Collagenous colitis, Lymphocytic colitis, Ischaemic colitis, Diversion colitis, Behçet’s disease, and Indeterminate colitis.

Crohn’s disease (CD) involves the patient’s immune system attacking the tissues of the gastrointestinal tract, which leads to chronic inflammation within the bowel. While the exact mechanism by which this disease works is still not completely understood and robustly debated, Crohn’s disease was originally thought to be an autoimmune disease in which the immune system recognizes some kind of surface protein in the gastrointestinal tract as foreign and then attacks it. However, genetic studies of CD, linked with clinical and immunological studies have shown that this is not the case. Instead, CD seems to be due to a poor innate immunity so that the bowel has an accumulation of intestinal contents that breach the lining of the gastrointestinal tract, resulting in chronic inflammation. A seminal paper by Daniel Marks and others in the Lancet in 2006 provided hard evidence that this is the case. When Marks and others tested the white blood cells from CD patients and their ability to react to foreign invaders, those cells were sluggish and relatively ineffective. Therefore, Crohn’s seems to be an overactivity of the acquired immunity to make up for poor innate immunity.

Given all that, one of the biggest, most painful consequences of CD are anal fistulas. If those sound painful it’s because they are. A fistula is a connection between to linings in your body that should not normally be connected. In CD patients, the anus and the attached rectum get kicked about by excessive inflammation and tears occur. These tears heal, but the healing can cause connections between linings that previously did not exist. Therefore fecal material not comes out of the body in more than one place. Sounds disgusting? It gets worse. Those areas that leak feces are not subject to extensive pus formation and they must be fixed surgically. But how do you fix something that is constantly inflamed? It’s an ongoing problem in medicine.

Enter stem cells to the rescue, maybe. In Spain, a multicenter clinical study has just been published that shows that fat-derived mesenchymal stem cells might provide a better way to treat these fistulas in CD patients. Mesenchymal stem cells have the ability to suppress inflammation, and for that reason, they are excellent candidates to accelerate healing in cases such as these.

Galindo and his group took 24 CD patients who had at least one draining fistula (yes, some have more than one) and gave them 20 million fat-derived mesenchymal stem cells. These cells were extracted from someone else, which is an important fact, since liposuction procedures on these patients might have added to their already surfeit of inflammation.

For this treatment, the cells were administered directly on the lesion, which is almost certainly important. If the closing of the fistula was incomplete after 12 weeks, then the patients were given another dose of 40 million fat-derived mesenchymal stem cells right on the lesion. All these patients were followed until week 24 after the initial stem cell administration.

The results were very hopeful. There were no major adverse effects six months after the stem cell treatment. This is a result seen over and over with mesenchymal stem cells – they are pretty safe when administered properly. Secondly, full analysis the data showed that at week 24 69.2% of the patients showed a reduction in the number of draining fistulas. Even more remarkably, 56.3% of the patients achieved complete closure of the treated fistula. That is just over half. Also, 30% of the cases showed complete closure of all existing fistulas. These results are exciting when you consider the criteria they used for complete closure: absence of draining pus through its former opening. complete “re-epithelization” of the tissue, which means that the lining of the tissue is healed, looks normal and is properly attached to the proper neighbors, and magnetic resonance image (MRI) scans of the region must look normal. For these patients, the MRI “Score of Severity,” which is a measure of the structural abnormality of the anal region, showed statistically significant reductions at week 12 with a marked reduction at week 24. Folks that’s good news.

Galindo interprets his results cautiously and notes that this is a small study, which is true. He also states that the goal of this study was to ascertain the safety of this technique, and when it comes to safety, this technique is certainly safe. When it comes to efficacy, another larger study is required that specifically examined the efficacy of this technique. Galindo is, of course, quite correct, but this is certainly a very exciting result, and hopefully these cells will get further chances to “strut their therapeutic stuff.”

See de la Portilla F, et al Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial.  Int J Colorectal Dis. 2013 Mar;28(3):313-23. doi: 10.1007/s00384-012-1581-9. Epub 2012 Sep 29.

Stem Cells Derived from Fat Show Promise for Regenerative Medicine


A detailed review article in the June issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons, has examined the safety and clinical efficacy of fat-derived stem cells. Stem cells from fat, also known as ACSs, are a promising source of cells for use in plastic surgery and regenerative medicine, according to this review, but there are still many questions that remain about them. Much more research is needed in order to completely establish the safety and effectiveness of ASC-based therapies in human patients. The review article was written by ASPS Member Surgeon Rod Rohrich, MD of University of Texas Southwestern Medical Center, Dallas, and his colleagues (Dr. Rohrich is Editor-in-Chief of Plastic and Reconstructive Surgery).

ASCs are very easily procured from humans, since simple procedures such as liposuction can provide more than enough material for therapies. On the average, one gram of fat yields about 5,000 stem cells, whereas the yield from the same quantity of bone marrow is about 1,000 cells (B. M. Strem, K. C. Hicok, M. Zhu et al., “Multipotential differentiation of adipose tissue-derived stem cells,” Keio Journal of Medicine, vol. 54, no. 3, pp. 132–141, 2005.). Once isolated from the fat, ASCs have the capacity to form fat cells, but also bone, cartilage and muscle cells.

From a therapeutic standpoint, ASCs promote the development of new blood vessels (angiogenesis). ASCs are also not recognized by the immune system and they seem to staunch inflammation. According the Dr. Rohrich and is co-authors, “Clinicians and patients have high expectations that ASCs may well be the answer to curing many recalcitrant diseases or to reconstruct anatomical defects.”

Fortunately, there is great interest in ASCs, and this means that the number of studies that examine ASCs or utilize them for experimental treatments have soared. Unfortunately, there is continued concern about the “true clinical potential” of ASCs. In the words of this new article, “For example, there are questions related to isolation and purification of ASCs, their effect on tumor growth, and the enforcement of FDA regulations.”

Rohrich and others conducted a rather in-depth review of all known clinical trials of ASCs. Thus far, most studies have been performed in Europe and Korea, and only three in the United States, to date. This reflects the stringency of FDA regulations.

Most ASC clinical trials to date have been examined the use of ASCs in plastic surgery. In this case, plastic surgeon-researchers have used ASCs for several types of soft tissue augmentation (breast augmentation, especially after implant removal and regeneration of fat in patients with abnormal fat loss or lipodystrophy). Studies exploring the use of ASCs to promote healing of difficult wounds have been reported as well. ASCs have also been used as in so-called soft tissue engineering or tissue regeneration. In these cases, the results have been inconclusive.

Other medical specialties have also made use of ASCs as treatments for other types of medical conditions. For example, ASCs have been studied for used to treat certain blood and immunologic disorders, heart and vascular problems, and fistulas (abnormal connection between an organ, vessel, or intestine and another structure). There are some other studies that have examined the use of ASCs for generating new bone for use in reconstructive surgery. A few studies have reported promising preliminary results in the treatment of diabetes, multiple sclerosis, and spinal cord injury. Perhaps one of the most encouraging results was the complete absence of serious adverse events related to ASCs in any of these studies.

These results are encouraging, but all of these applications are in their infancy. Globally speaking, less than 300 patients have been treated with ASCs, and no standardized protocol exists for the preparation or clinical applications of ASCs. Additionally, there is no consensus as to the number of ASCs required per treatment, or how many treatments are required for the patient to show clinical improvement. Thus Rohrich and his colleagues have taken a “proceed with caution approach.” They conclude that “further basic science experimental studies with standardized protocols and larger randomized controlled trials need to be performed to ensure safety and efficacy of ASCs in accordance with FDA guidelines.”