Ulcerative colitis (UC) is an autoimmune condition characterized by chronic inflammation of the colon. Conventional treatments involve surgical procedures and glucocorticoids, which, despite providing symptom relief, can lead to many adverse effects. The limitations of these treatments necessitate the exploration of novel therapeutic strategies. The therapeutic potential of mesenchymal stem cells (MSCs) in immunomodulation and tissue regeneration is well-recognized. However, challenges such as poor post-transplant survival rates and ethical concerns limit their clinical applicability. Ecto-mesenchymal stem cells-conditional medium (EMSCs-CM), known for its potent anti-inflammatory properties, presents a promising alternative. The development of tissue engineering and colon-targeted drug delivery systems using biodegradable materials like γ-polyglutamic acid (γ-PGA) has further enhanced the potential of EMSCs-CM in UC treatment.
In a new study published in BioMedical Materials Journal led by Dr.Wenjing Yang, Xingxing Zhang, Liuyao Qi, Dr. Zhe Wang, Dr. Weijiang Wu, Wenjing Feng, Yahan Gu from the School of Medicine at Jiangsu University, the researchers conducted a series of comprehensive experiments to evaluate the effectiveness of the newly developed EMSCs-CM hydrogel (EMSCs-CM-Gel) in the treatment of UC. The authors isolated EMSCs from the nasal septum of mice, cultured them, and identified them using specific markers like S100 and Nestin. They successfully obtained high-purity EMSCs, confirmed by their expression of neural crest marker Nestin and ectodermal MSC marker S100. Afterward, they cultured EMSCs in a pure medium, collected the conditioned medium, and concentrated it using freeze-drying. Moreover, they Identified the presence of anti-inflammatory factors and extracellular vesicle markers (like CD9, CD81) in the EMSCs-CM, indicating its rich composition of therapeutic agents.
The team evaluated EMSCs-CM’s Effects In Vitro and tested the proliferative and protective effects of EMSCs-CM on intestinal epithelial cell 6 (IEC-6) using the CCK-8 assay, immunofluorescence, and Calcein-AM staining and found that EMSCs-CM enhanced the growth of IEC-6 cells and showed a protective effect against lipopolysaccharide (LPS)-induced damage. The authors formulated innovative EMSCs-CM-Gel by combing EMSCs-CM with γ-PGA hydrogel, crosslinked using TG2. This hydrogel is characterized by its negative charges, which ensure adherence to the positively charged inflamed colon tissue. This feature enables the continuous release of EMSCs-CM at the site of damage, enhancing the therapeutic efficacy. The EMSCs-CM-Gel was tested its stability and targeting ability in simulated gastrointestinal conditions and noticed the EMSCs-CM-Gel demonstrated increased stability in the gastrointestinal environment and exhibited targeted delivery to the colon. The gel’s ability to localize and continuously release EMSCs-CM in the damaged colon mucosa offers a targeted approach, minimizing gastrointestinal damage and maximizing therapeutic benefits. This innovative colon-targeting strategy represents a significant advancement in UC treatment.
Professor Wenjing Yang and colleagues evaluated the in vivo efficacy in a DSS-induced UC mouse model where EMSCs-CM-Gel was orally administered to mice with DSS-induced UC and evaluated its therapeutic effects compared to controls. They found mice treated with EMSCs-CM-Gel showed significant alleviation of UC symptoms, including reduced weight loss, lower disease activity index scores, and less colon shortening. To further validate their therapeutic efficacy, the authors performed histological examination of colon tissues using H&E staining and showed EMSCs-CM-Gel treatment preserved the normal microstructure of intestinal crypts, reduced inflammatory cell infiltration, and increased goblet cell numbers. Additionally, western blot and immunohistochemical staining assessed the levels of key proteins like IL-10, TNF, and mucin in colon tissues and found an increased expression of anti-inflammatory proteins (IL-10) and decreased levels of inflammatory markers (TNF) in the EMSCs-CM-Gel group. This indicated a reduction in inflammation and a protective effect on the colon epithelium. These findings indicate EMSCs-CM-Gel works by binding to the positively charged proteins at the injury site, thanks to its negative charge. This ensures a prolonged dwelling time in the intestine, allowing for sustained release of therapeutic agents. The upregulation of IL-10 and downregulation of pro-inflammatory cytokines in the treated mice indicate a powerful anti-inflammatory effect, contributing to mucosal healing and barrier repair.
While EMSCs-CM-Gel shows promise for UC treatment, further research is needed to fully understand its mechanisms and long-term efficacy. The interaction of EMSCs-CM with the local microenvironment and the specific pathways involved in tissue repair and inflammation modulation require deeper investigation. Additionally, large-scale clinical trials are necessary to validate these findings in human patients and to establish the safety and efficacy of this novel treatment. In conclusion, the development of EMSCs-CM-Gel by Professor Wenjing Yang and team represents a significant milestone in UC therapy with EMSCs-CM-Gel effectively suppressed inflammation, protected the colon epithelium, and promoted repair in UC.
Yang W, Zhang X, Qi L, Wang Z, Wu W, Feng W, Gu Y. Colon-targeted EMSCs conditional medium hydrogel for treatment of ulcerative colitis in mice. Biomed Mater. 2023;18(6). doi: 10.1088/1748-605X/acfadb.