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Pan-myeloid Differentiation of Human Cord Blood Derived CD34+ Hematopoietic Stem and Progenitor Cells
Published on: August 9, 2019
Differential expression of P-glycoprotein in cord blood and peripheral blood lymphocyte subpopulations
S Aggarwal1, A Gupta, T Tsuruo
1UNIV CALIF IRVINE,DIV BASIC & CLIN IMMUNOL,C 240,IRVINE,CA 92717. WESTERN MED CTR,SANTA ANA,CA.
Insights
Cord blood T cells show lower P-glycoprotein (P-gP) expression and function compared to adult T cells, leading to increased sensitivity to cyclosporin A (CSA). Further research is needed to determine the physiological role of this difference.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- P-glycoprotein (P-gP), encoded by MDR1, is crucial for secreting various molecules like hormones and drugs.
- Cord blood lymphocytes are functionally immature and exhibit heightened sensitivity to immunosuppressants such as cyclosporin A (CSA).
Purpose of the Study:
- To compare the surface expression, function, and messenger RNA (mRNA) levels of P-gP in cord blood versus peripheral blood T cells.
- To assess the functional consequences of P-gP differences on T cell sensitivity to CSA.
Main Methods:
- Flow cytometry was used to quantify P-gP surface expression on CD4(+) and CD8(+) T cell subsets (naive and memory) from cord blood and peripheral blood.
- MDR1 mRNA levels were analyzed in mononuclear cells.
- Rhodamine 123 (Rh123) accumulation assay was performed to measure P-gP efflux function.
- CSA sensitivity was determined by measuring T cell proliferation.
Main Results:
- Significantly lower P-gP surface expression was observed on cord blood T cells (1-2%) compared to peripheral blood T cells (7-10%).
- MDR1 mRNA levels were also reduced in cord blood mononuclear cells.
- Cord blood T cells exhibited higher intracellular Rh123 accumulation, indicating reduced P-gP efflux function.
- Cord blood T cell subsets showed markedly greater sensitivity to CSA than peripheral blood T cells.
Conclusions:
- Cord blood T cells possess diminished P-gP expression and function compared to adult peripheral blood T cells.
- This reduced P-gP activity contributes to the heightened sensitivity of cord blood T cells to CSA.
- The physiological significance of decreased P-gP in cord blood warrants further investigation.
Abstract:
P-glycoprotein (P-gP) is a 170 kDa glycoprotein encoded by MDR1 that appears to be involved in the secretion of a large number of molecules including hormones, cyclosporin A (CSA) and cytokines. Cord blood lymphocytes are functionally immature and are sensitive to CSA. Therefore, we compared the surface expression and function of P-gP in cord blood and peripheral blood CD4(+) and CD8(+) T cells and their naive (CD45RA(+)) and memory (CD45RO(+)) subsets. We observed that only 1% of cord blood CD4(+) and 2% CD8(+) cells expressed P-gP as compared to 7% and 10% respectively of peripheral blood from young controls. In addition, MDR1 mRNA levels were also decreased in cord blood mononuclear cells as compared to peripheral blood from young controls. The efflux function of P-gP was measured by intracellular accumulation of rhodamine 123 (Rh123, a substrate for P-gP) in the presence or absence of CSA. A higher accumulation of Rh123 was observed in cord blood CD4(+) and CD8(+) and their naive and memory cell subtype as compared to those in peripheral blood. Furthermore, cord blood CD4(+) and CD8(+) T cell subsets exhibited greater sensitivity towards CSA (% increase: 119 and 188 respectively) as compared to peripheral blood (44 and 89 respectively). A physiological role of decreased P-gP expression and function in cord blood remains to be determined.
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