The Human Intestine as a New Reservoir for Functional Hematopoietic Stem and Progenitor Cells

Review of “Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that are Maintained by a Circulating Pool” from Cell Stem Cell by Stuart P. Atkinson 

Fascinating recent research from the laboratory of Megan Sykes (Columbia University, New York, NY, USA) reported long-term mixed chimerism of donor and recipient blood [1, 2] following intestinal transplantation in human patients [3]. While studies have reported CD45/CD34-positive hematopoietic stem and progenitor cells (HSPCs) in the adult human small intestine [4] and liver [5], we currently lack a detailed description of the intestinal load of HSPCs throughout the intestine and how they contribute to the observed chimerism. However, a new Cell Stem Cell report from Fu et al. now establishes that intestinal graft-resident HSPCs contribute to long-term multilineage blood chimerism after human intestinal transplantation, a finding that may allow improved tolerance in transplant recipients [6].

The authors’ assessment of chimeric peripheral blood cell phenotypes in intestinal allografts patients over five years revealed the presence of donor lymphocyte phenotypes and therefore suggested a contribution from graft-derived HSPCs. Analysis of intestinal tissues subsequently highlighted reservoirs of donor-derived HSPCs (HSCs and multiple different progenitor types) residing in the intestinal mucosa, Peyer’s patches, mesenteric lymph nodes, and the liver.  Colony-forming-cell assays, long-term-culture-initiating-cell assays, and analysis in humanized mouse models demonstrated that intestinal HPSCs presented similarities to bone marrow HSPCs at the phenotypic and differentiation potential levels. 

Subsequent studies of circulating post-transplant donor T cells also suggested functionality and acquired immune tolerance via selection in recipient lymphoid organs, raising the possibility that recipient-specific regulatory T cells (Tregs) can promote tolerance of graft-versus-host T cells from the intestinal allograft. Additionally, the authors also discovered that donor HSPCs became gradually replaced from a circulating pool of recipient HSPCs that home to the intestine. 

Overall, the authors ascertained that the presence of functional HPSCs in the human intestine lies behind the persistence of donor mixed chimerism in intestinal transplantation patients; a finding that may have important implications for the complications (e.g., graft-versus-host disease) that arise in transplant recipients. The authors now hope to discover whether the intestine represents a significant residence for HSPCs under physiological conditions and explore the contribution of graft-derived HSPCs to sustained mixed chimerism in the blood as a means of promoting allograft tolerance in intestinal transplantation recipients.

For more on how the human intestine acts as a reservoir for functional hematopoietic stem and progenitor cells, stay tuned to the Stem Cells Portal!

References

1. Fu J, Zuber J, Shonts B, et al., Differing Mechanisms for Early Versus Persistent Donor T cell Chimerism in Peripheral Blood of Human Intestinal Transplant Recipients. Transplantation 2017;101:S63-S64.
2. Zuber J, Rosen S, Shonts B, et al., Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD. American Journal of Transplantation 2015;15:2691-2703.
3. Kubal CA, Mangus RS, and Tector AJJCGR, Intestine and Multivisceral Transplantation: Current Status and Future Directions. Current Gastroenterology Reports 2015;17:5.
4. Lynch L, O’Donoghue D, Dean J, et al., Detection and Characterization of Hemopoietic Stem Cells in the Adult Human Small Intestine. Journal of Immunology 2006;176:5199-5204.
5. Wang XQ, Lo CM, Chen L, et al., Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver. Hepatology 2012;56:1557-1566.
6. Fu J, Zuber J, Martinez M, et al., Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool. Cell Stem Cell 2019;24:227-239 e8.