An Oregon Health & Science University study is adding credence to an increasingly popular theory that fusion is what bonds stem cells with bone marrow cells to regenerate organ tissue.
Scientists in the OHSU School of Medicine found that transplanted cells derived from adult bone marrow can fuse with intestinal stem cells of both normal and diseased tissue comprising the cellular lining of intestinal walls, known as the epithelium. The findings, reported recently in the Proceedings of the National Academy of Sciences, point to the integral role of bone marrow-derived cells in not only regeneration of damaged tissue, but also disease progression.
"It's the first observation that there's fusion at the level of stem cells," said the study's corresponding author, Melissa Wong, Ph.D., assistant professor of dermatology, and cell and developmental biology. "Second, we're seeing cell fusion in tumors and we believe that this concept is an underappreciated mechanism for promoting tumor growth. Our findings have implications on how tissues regenerate and how, in the process of this regeneration, cells may become prone to future problems. "
Although the tumor in her study did not "initiate" tumors or become malignant, Wong believes the fusion process is one explanation for how tumors acquire genetic instability and have the potential to give rise to malignant cancer.
One promising result could be in better understanding the careful balance between rapid and effective regeneration after tissue injury, and minimizing the risk of cancer. This balance can be examined in mouse models of inflammatory bowel disease, where, like humans, epithelial damage and chronic tissue repair occurs.
"Ten percent of patients with inflammatory bowel disease go on to get colorectal cancer," Wong said. "We think that the bone marrow cells aid in repair of the epithelium, but the cell fusion hybrids that remain are generally unstable. Fusion may be an underlying molecular explanation of why these cells might be more susceptible to cancer development."
In the PNAS study, Wong and her colleagues transplanted bone marrow cells from female mice into a male mouse model of intestinal cancer. The donor-derived cells were readily detected in the intestinal tumors of the male mice.
To show that the transplanted donor cells fused with the tumor cells, the scientists detected proteins or markers from both the female donor and male recipient cells in tumors. The only way both donor and recipient markers could be present in a single cell, or colocalized, would be if the two cells fused.
One test to prove cell fusion involved looking for the presence of Y chromosomes, or male-characteristic DNA, within the female donor cells marked with a green fluorescent protein. About 60 percent of the epithelial cells were positive for both donor and recipient cell markers. A second test confirmed colocalization using a confocal microscope, which can scan a single cell layer of intestinal cells for the presence of both the green fluorescent protein, indicating female donor cells, and an enzyme from the male recipient cells.
Wong said, "Our paper is unique because it's the first example that cell fusion occurs in the epithelial compartment of a tumor."
Other OHSU studies in recent years are giving weight to the fusion theory. A series of discoveries since 2000 by study co-author Markus Grompe, M.D., professor of molecular and medical genetics, and pediatrics, OHSU School of Medicine, and director of the OHSU's Oregon Stem Cell Center at OHSU, showed that blood-forming stem cells derived from bone marrow, called hematopoietic stem cells, cure liver disease in mice through cell fusion rather than transdifferentiation of the transplanted stem cells.
Wong acknowledges fusion is still a new concept. But it's gaining popularity as a way of explaining the molecular mechanisms that may be at work in regenerating rapidly turning over damaged tissue, or may even be implicated in disease progression.
"The intestinal lining is the protective barrier between your body and the outside environment. Therefore, it sees all of the offensive contaminants that you ingest, from the beer you drink to the charbroiled hamburger you eat, that can induce mutations in the cells. The gut protects itself by rapidly turning over its epithelial cells. Plus, when there is damage to the surface lining, it is critical that regeneration and reestablishment of the barrier occurs rapidly. We think that cell fusion with bone marrow cells is the body's way of jump-starting that regeneration of the epithelium," she said.
The study was funded by the National Institutes of Health. Other authors in the OHSU School of Medicine were Adnan Rizvi, M.D., surgical resident in dermatology; John Swain, research assistant in dermatology; Paige Davies, Ph.D., postdoctoral fellow of dermatology; Alexis Bailey, research assistant in medicine (endocrinology, diabetes and clinical nutrition); Adria Decker, graduate research assistant in molecular and medical genetics; Holger Willenbring, M.D., former postdoctoral fellow of molecular and medical genetics; and William Fleming, M.D., Ph.D., associate professor of medicine (hematology and medical oncology) and cell and developmental biology.