Detection and Characterization of Hemopoietic Stem Cells in the Adult Human Small Intestine

Abstract

The concept of lymphoid differentiation in the human gastrointestinal tract is controversial but is the focus of this study, which examined adult human small intestinal tissue for the presence of CD34+CD45+ hemopoietic stem cells (HSCs) and lymphoid progenitors. Flow cytometry demonstrated that over 5% of leukocytes (CD45+ cells) isolated from human gut were HSCs coexpressing CD34, a significantly higher incidence than in matched peripheral blood or control bone marrow. HSCs were detected in cell preparations from both the epithelium and lamina propria of all samples tested and localized to the intestinal villous and crypt regions using immunofluorescence. A high proportion of gut HSCs expressed the activation marker CD45RA, and few expressed c-kit, indicating ongoing differentiation. The vast majority of intestinal HSCs coexpressed the T cell Ag, CD7 (92% in the epithelium, 80% in the lamina propria) whereas <10% coexpressed the myeloid Ag CD33, suggesting that gut HSCs are a relatively mature population committed to the lymphoid lineage. Interestingly, almost 50% of epithelial layer HSCs coexpressed CD56, the NK cell Ag, compared with only 10% of the lamina propria HSC population, suggesting that the epithelium may be a preferential site of NKR+ lymphoid differentiation. In contrast, bone marrow HSCs displayed low coexpression of CD56 and CD7 but high coexpression of CD33. The phenotype of intestinal HSCs, which differs significantly from circulating or bone marrow HSCs, is consistent with a role in local lymphoid development.

Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants, Without GVHD

“…However, liver and intestinal hematopoietic progenitors may differ in their multilineage differentiation potential. Although liver hematopoietic stem cells can give rise to multiple lineages, including lymphoid (44) and myeloid (45) cells, human gut-derived progenitors cells are almost exclusively lymphoid (CD7 positive) (46) and therefore only able to generate T cells (47). Consistent with this observation, in contrast to liver and multivisceral recipients, liver-free intestinal transplant recipients never displayed myeloid macrochimerism in our study.…”

Activated Notch Supports Development of Cytokine Producing NK Cells Which Are Hyporesponsive and Fail to Acquire NK Cell Effector Functions

“…Another example of extramedullary microenvironment specific lymphoid development is found in gastrointestinal mucosa, where extensive expression of Notch and their ligands are found [50]. The human small intestine is a site of CD34 + CD7 + lymphoid precursor development, not generally present in the circulation, suggesting that the gut may be an important site of early lymphoid differentiation [51]. These findings support the notion that Notch ligand expressing tissues play a role in NK cell differentiation and ultimately in the process of NK cell education.…”

Human natural killer cells

“…24 Similar cells have subsequently been described in mucosa-associated lymphoid tissue in the gut. 25,26 This selective enrichment of both CD34 ϩ CD45RA ϩ pre-NK cells and CD56 bright NK cells within SLT relative to BM or blood, along with an abundance of dendritic cells (DCs) and other antigen presenting cells (APCs) that express membranebound IL-15, 27 which is required for NK-cell maturation, [28][29][30] suggested that SLT may be a site for NK-cell development in vivo. Indeed, a search in SLT for phenotypically and functionally distinct cell populations that represent stages along the NKcell developmental pathway from CD34 ϩ CD45RA ϩ HPCs to CD3 Ϫ CD56 bright NK cells in situ was successfully undertaken (Figure 2).…”