Scientists at Columbia University’s Vagelos College of Physicians and Surgeons report a surprising new finding: the human intestine may provide up to 10% of blood cells in circulation from its own reservoir of blood-forming stem cells. Previously, blood cells were thought to be created exclusively in the bone marrow from a special population of hematopoietic stem cells, according to the researchers who say their discovery may eventually improve the success rates of human intestinal transplants.
The team’s study (“Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that are Maintained by a Circulating Pool”) appears in Cell Stem Cell.
“Human intestinal transplantation often results in long-term mixed chimerism of donor and recipient blood in transplant patients. We followed the phenotypes of chimeric peripheral blood cells in 21 patients receiving intestinal allografts over 5 years. Donor lymphocyte phenotypes suggested a contribution of hematopoietic stem and progenitor cells (HSPCs) from the graft. Surprisingly, we detected donor-derived HSPCs in intestinal mucosa, Peyer’s patches, mesenteric lymph nodes, and liver,” wrote the investigators.
“Human gut HSPCs are phenotypically similar to bone marrow HSPCs and have multilineage differentiation potential in vitro and in vivo. Analysis of circulating post-transplant donor T cells suggests that they undergo selection in recipient lymphoid organs to acquire immune tolerance. Our longitudinal study of human HSPCs carried in intestinal allografts demonstrates their turnover kinetics and gradual replacement of donor-derived HSPCs from a circulating pool. Thus, we have demonstrated the existence of functioning HSPCs in human intestines with implications for promoting tolerance in transplant recipients.”
Intestinal transplantation is the only long-term option for patients with Crohn’s and other diseases if their intestines fail. But high rejection rates and life-threatening complications from immunosuppression have limited the success of human intestinal transplantation.
When a person receives a transplanted organ, the immune system often recognizes the new organ as foreign and destroys it. Immunosuppressive drugs blunt these responses, but that makes the patient much more susceptible to infections and other complications.
Analysis of circulating white blood cells in patients after intestinal transplantation suggests that the cells derived from the donated intestine have matured and been educated in the recipient to be tolerant of the recipient’s own tissues. Likewise, white blood cells made by the recipient after the transplant may be educated to be tolerant of the donated tissue.
“We are clearly showing that there’s immunological cross-talk between the two sets of blood cells that protects the transplant from the patient’s immune system and protects the patient from the transplant,” said Megan Sykes, M.D., director of the Columbia Center for Translational Immunology.
The hematopoietic stem cells in the intestine are eventually replaced by a circulating pool from the recipient, the researchers also found.
Because patients with more donor blood cells had lower organ rejection rates, the results point toward new strategies for managing organ transplantation.
The intestine’s reservoir of blood-forming stem cells was discovered when researchers noticed that the blood of patients who had received intestinal transplants contained cells from the donor. The researchers tracked the donor’s blood cells back to their source: hematopoietic stem cells in the donated intestine.
The blood cells created from cells in the donor’s intestine also may be beneficial to the transplant recipient. The more donor blood cells a patient had in circulation, the less likely they were to reject their transplants.
“It’s possible that patients with a high level of donor cells may not require as much immunosuppression as they are currently getting,” said Dr. Sykes, “and reducing immunosuppression could improve outcomes.”
Seeding transplanted organs with additional hematopoietic stem cells from the donor may also increase donor-recipient cross-talk and boost tolerance of the transplant.
“That could improve the lives of transplant patients dramatically,” continued Dr. Sykes. “Our ultimate goal is to get immune tolerance, which would allow us to remove immunosuppression altogether and have the graft treated as self by the patient. That’s really the Holy Grail.”
The researchers are planning a study that will try to boost the number of hematopoietic stem cells delivered during intestinal transplantation, hopefully leading to higher levels of donor blood cells in circulation, immune tolerance, and a reduced need for immunosuppressive drugs. Other types of transplants may benefit from similar interventions, even for organs that don’t appear to carry their own reservoirs of hematopoietic stem cells.
This study analyzed 21 patients who had received intestinal transplants. Although the finding of a novel population of hematopoietic stem cells is exciting, it does not yet justify changes in the current standard of care, noted the researchers.