Organoid-based regenerative medicine for inflammatory bowel disease
Recent advance in stem cell biology has added intestinal stem cells (ISCs) as a new player in this field.
The treatment of IBD has dramatically improved in the past decade, mainly by the outstanding clinical effect of biologic agents such as anti-TNF-α antibodies . Those therapies were targeted mostly to control the inflammation that arises at the mucosa of IBD patients. However, less attention had been paid to the recovery of the tissue damage that may manifest as intestinal ulcers. Recent clinical studies have clearly shown that “mucosal healing” is an utmost requirement to achieve long-term remission in IBD patients . “mucosal healing” indicates complete restore of the mucosal structure and function. Therefore, a high demand exists for an alternative treatment that can promote tissue regeneration of refractory IBD patients.
The intestinal mucosa consists of three cell populations: lymphocytes, mesenchymal cells, and epithelial cells. In the past years, many studies have tried to use hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs) for the treatment of IBD. Recent advance in culture methods has newly added ISCs as another candidate cell source for regenerative medicine in IBD patients. A more extensive choice of stem cell source may help to establish an effective stem cell-based alternative therapy for refractory IBD patients.
Base on those previous studies, intestinal organoids can now be considered as one of the candidate sources to repair the ulcers that may appear in refractory IBD patients. One of the strategies that may be taken for such treatment is autologous, endoscopic transplantation of ISCs (Fig. 1). ISCs can be collected from the intact lesion of a patient through the endoscopic biopsy, and then expanded in vitro by the established organoid culture method. After growing them to a desired number of cells, they can be transplanted onto the target site through an endoscopic delivery method. Presumably, it would be better to reduce or achieve good control of the mucosal inflammation before the organoid transplantation, to guarantee high engraftment efficiency.
However, further researches and several technical developments are required to enable such a treatment (Table 1). At the cell culture level, we need to know whether the in vitro properties of ISCs that were derived from IBD patients is comparable to those derived from healthy donors. A recent study by our group has shown that organoids derived from active lesions of CD patients exhibit comparable growing potential compared to those from healthy donors and maintain mostly same ISC-specific gene expression profile at the single-cell level . Besides, organoids can change their morphology or its ISC-content depending on the culture environment determined mainly by extracellular matrix and growth factors (Fig. 2). Further studies using transplantation model of colitis mice may reveal the optimized culture condition for transplantation therapy.
Then what would be the expected benefit for those patients who underwent the ISC transplantation? The first may be the improvement in mucosal healing rate that would directly lead to an improved prognosis. The second will be the possible reduction of the risk in developing colitis-associated cancer . As those cancers may arise from the accumulation of genetic as well as epigenetic changes within the ISCs through their long-term exposure to the inflammatory environment, replacing such an exhausted ISCs to those fresh and lively ISCs that were grown in the most ideal and stable environment would possibly have the potential to reduce the initiation of colitis-associated cancers.
Read full research paper Organoid-based regenerative medicine for inflammatory bowel disease.
Download research: Organoid-based regenerative mjedicine for inflammatory bowel disease