In vitro evidence for the presence of hematopoietic stem cells in the adult human liver

Previous studies have identified novel lymphoid phenotypes in the adult hum an liver and provided evidence to suggest that lymphoid differentiation can occur locally in this organ. The aim of this study was to examine the adul t human liver for the presence of hematopoietic stem cells that may provide the necessary precursor population for local hematopoietic and lymphoid di fferentiation. Hepatic mononuclear cells (HMNC) were extracted from normal adult liver biopsy specimens using a combination of mechanical disruption a nd enzymatic digestion. The stem cell marker CD34 was found on 0.81% to 2.3 5% of isolated HMNCs by flow cytometry. CD34(+) HMNCs were positively selec ted using magnetically labeled beads, and the enriched population was furth er examined for surface markers characteristically expressed by immature he matopoietic cells and early progenitors. CD45 was expressed by 49% (+/-23%) of CD34(+) HMNCs, indicating their hematopoietic origin. CD38, one of the first markers to be expressed by developing progenitor cells was found on 5 0% (+/-22%) of CD34(+) HMNCs indicating the presence of both pluripotent st em cells and committed precursors, The majority (90%) of CD34(+) HMNCs coex pressed the activation marker human leukocyte antigen DR, consistent with a ctively cycling cells. Functional maturation of these hepatic progenitors w as shown by the detection of multilineage hematopoietic colony formation af ter tissue culture. Erythroid (BFU-E), granuloctye-monocyte (CFU-GM), and m ixed colonies (CFU-GEMM) were detected after culture of unseparated HMNCs a nd the enriched CD34(+) HMNC population; 14.3 +/- 13.2 (mean +/- SD) BFU-E, 3.1 +/- 3.1 CFU-GM, and 0.4 +/- 0.9 CFU-GEMM per 1 x 10(5) unseparated HMN Cs and 16.0 +/- 9.5 BFU-E and 1.7 +/- 0.9 CFU-GM were identified per 2.4 x 10(3) CD34(+) HMNCs plated. The detection of surface markers characteristic of immature hematopoietic cells and colony formation in tissue culture pro vides evidence for the presence of hematopoietic stem cells and early proge nitor cells in the adult human liver. This would suggest that the adult hum an liver continues to contribute to hematopoiesis and may be an important s ite for the differentiation of lymphohematopoietic cells involved in diseas e states, such as autoimmune hepatitis and graft rejection after liver tran splantation.