Stem Cells from Young Mice Heal Stomach Ulcers in Old Mice

When it comes to the question of whether young stem cells and a young tissue environment are necessary for the success of stem cell therapies, there is evidence to support all of the possible answers. It is a confusing picture at the moment, and it is very possible that the answer varies by cell type. Since the best option for therapy is to use the patient's own cells, it would be good to find that cell therapies can work effectively and produce meaningful benefits even when both cells and patient are old. In some studies researchers have seen little difference in short term outcomes between young and old individuals, which is the more surprising of the possible results: the intuitive expectation is that age-related damage and the signaling changes that suppress stem cell activity in response to that damage will make all forms of cell therapy less effective in old individuals. In the research linked here, the results are more in line with expectations, in that young stem cells work to promote regeneration where old stem cells do not. This sort of experimentation will in time lead to a list of things that must be changed and corrected in stem cells, probably differing by tissue type, in order to make them more effective when transplanted into older individuals:

During aging, changes in the stomach result in gastric tissue that is less capable of repairing injury correctly. These changes include decreased gastric acid secretion, cell motility, and proliferation. In addition, angiogenesis, a fundamental process essential for wound healing, is impaired with advanced age. Such pathophysiological changes are believed to result in disrupted repair in response to chronic ulceration in the elderly that can be exacerbated during chronic insults such as Helicobacter pylori infection or nonsteroidal anti-inflammatory drug administration. In elderly patients there is a strong association between ulceration with cancer or evolution of dysplasia into neoplasia. Renewal of gastric stem cells to produce committed progenitor cells that differentiate further into adult epithelial cell types is important for the structural integrity of the mucosa. However, relatively little is known regarding the age-related changes affecting gastric epithelial stem cells. Early studies have shown that in aged rats, stem cell proliferation and epithelial cell numbers are decreased compared with young animals, thus suggesting impaired tissue integrity in the aged stomach.

The origin of cells for repair of severe gastric epithelial injury has not received extensive attention. Recent investigations have indicated that loss of parietal cells, either from acute toxic injury or chronic Helicobacter infection, leads to the development of spasmolytic polypeptide/trefoil factor (TFF) 2-expressing metaplasia (SPEM) through transdifferentiation of chief cells into mucous cell metaplasia. In the face of continued inflammation and M2-macrophage influence, SPEM may progress to a more proliferative preneoplastic metaplasia. However, studies with acute injury have indicated that SPEM disappears after resolution of injury. No studies have addressed whether SPEM may contribute to the healing of gastric ulcers. We now report that SPEM represents a major reparative lineage responsible for wound healing after gastric ulcer injury.

Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium. Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration. Thus the healing of gastric ulcers in the aged stomach is promoted by the transplantation of gastric organoids.



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