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Mesenchymal stem cell therapy for inflammatory bowel disease: An updated review with
maintenance of remission
Maneesh Dave, MD, MPH1, Palashkumar Jaiswal, MBBS2, Fabio Cominelli, MD, PhD1
Author Affiliations:
1
Division of Gastroenterology and Liver Disease, University Hospitals, Case Western Reserve
University, Cleveland, Ohio, USA.
2
Division of Internal Medicine, John H Stroger Jr. Hospital of Cook County, Chicago, Illinois,
USA
Corresponding Author:
Maneesh Dave, MD, MPH
Division of Gastroenterology and Liver Disease
Case Western Reserve University
University Hospitals Case Medical Center
11100 Euclid Avenue, Cleveland Ohio 44106-5066
Phone # 216-844-1995 Fax# 216-844-7371
Email: [email protected]
Word Count: 194 words
Supplementary text
Method
Using our previously published research strategy, a systematic search of English and nonEnglish articles was performed with aid of PubMed (from 01/2015 to present) and Ovid (from
01/2015 to present) (1). We also identified additional studies by searching bibliographies and
abstracts presented at the Digestive Disease Week, American College of Gastroenterology,
European Crohn’s and Colitis Organization and United European Gastroenterology Week from
2015-2016. In order to increase the sensitivity of our search, we used free text words and MeSH
terms with and without Boolean operators (“AND” and “OR”). Studies were selected based on
the following inclusion criteria: (1) human studies, (2) included patients with IBD, (3) MSCs
were used for treatment of IBD, and (4) peer-reviewed article, letter, or abstract. Exclusion
criteria were (1) non-human studies and (2) use of total-body irradiation or myeloablative
regimen. With this particular search strategy, we found an additional 67 peer-reviewed articles
published since our previous publication and of these only 8 studies met the selection criteria.
From meeting abstracts and bibliographies we were able to find 2 more studies that have
satisfied our criteria.
Human and murine MSCs suppress inflammation in murine models of intestinal
inflammation
Multiple studies have demonstrated that murine derived adipose and bone marrow mesenchymal
stem cells (MSCs) can suppress inflammation in murine models of colonic inflammation(2-5).
Similarly, human MSCs from different sources have also been utilized to treat inflammation in
models of colonic inflammation in immune competent mice (supplementary table 1 for details)
(6-11). However, ambiguities in immunosuppressive property of MSCs are still present and
despite the data showing efficacy of human MSCs in treating inflammation in mice; many
investigators have questioned the rationale of using human cells in immunocompetent mice (12).
In the following section, we will briefly provide the advantages and disadvantages of modeling
human vs mice MSCs in preclinical models of intestinal inflammation (13).
Modeling human and murine MSCs in preclinical models of disease
Human and murine MSCs are considered immune-evasive and characteristically have low
expression of MHC II and costimulatory molecules- CD40, CD80 and CD86(14, 15). Despite
species compatibility, murine MSCs have many disadvantages for in vivo therapeutic studies as
1) it is very difficult to isolate a pure population of MSCs from bone marrow that are not
contaminated with other cells of mesenchymal lineage and, 2) in culture, murine MSCs tend to
immortalize and have genomic instability (16, 17). On the other hand, it is much easier to isolate
and propagate a pure population of human MSCs without genomic instability(13). A
disadvantage of using human cells in immunocompetent mice is the possibility of immune
rejection of human MSCs, though some studies have not found induction of immunological
response against human MSCs in murine models of colitis and this area needs further study (4).
Another challenging aspect of modeling MSC is that murine and human MSCs may not be
identical in their dominant mechanism (s) of immunosuppression and healing as is demonstrated
by indoleamine 2,3-dioxygenase (18, 19)_ENREF_20, an important pathway in human but not
murine MSCs in immunosuppression (20). Therefore, to overcome these challenges a
comparative biology approach to model human and murine MSCs in animal models has been
suggested. This approach involves treating a model of intestinal inflammation with both murine
and human MSCs for identification of the shared and differentially operating molecules and
pathways that contribute to healing with a focus on common pathways (eg prostaglandin E2) for
murine and human MSC. Another methodology, which is still in infancy, but could be
developed, is to use humanized mice for testing different regenerative medicine therapies
including MSCs for treatment of intestinal inflammation (21). We believe that a combination of
these approaches can overcome most of the limitations of modeling MSCs in mice, helping to
generate important mechanistic preclinical data to guide human MSC therapy and identify novel
molecules that promote tissue regeneration and healing.
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