Signaling pathways regulating self-renewal, differentiation, and multipotency of CD133+ umbilical cord blood stem cells

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Title: Signaling pathways regulating self-renewal, differentiation, and multipotency of CD133+ umbilical cord blood stem cells
Author: Margaret Corbett Howe
Abstract: Our goal is to increase the number of immature umbilical cord blood stem cells (UCBSCs ) for hematopoietic transplantation . Towards this goal , our lab adapted a culture technique to grow immature CD133+ UCBSCs (CD133+ cells ) . Although CD133+ cells proliferate rapidly in culture , a minority self -renew and remain CD133+ , while a majority differentiate and become CD133 - . Therefore , new strategies to identify and grow immature UCBSCs are important . Since little is known about signally mechanisms regulating self -renewal and differentiation of UCBSCs , we sought insight from embryonic stem cell (ESC ) literature to guide our studies . \r \nTo identify a population of UCBSCs that grow without differentiating , we focused on Oct -4 , a transcription factor essential for self -renewal in ESCs that we previously reported expression in UCBSCs . During our studies , new challenges in the field arose . Two isomers of Oct -4 were discovered , Oct -4A and Oct -4B 3 , in which only Oct -4A conferred the ability of ESCs to self -renew 4 . We redesigned our experiments to detect Oct -4A and discovered that freshly isolated CD133+ cells expressed Oct -4A mRNA and protein . Since these cells proliferated in culture , they lost expression of adult stem cell markers including CD133 , and gained markers of hematopoietic differentiation . However , Oct -4A mRNA and protein were expressed regardless of the differentiation status . Therefore , Oct -4A , despite its essential roles in ESCs , neither defined nor conferred self -renewal of CD133+ cells . \r \nTo discover strategies to grow immature CD133+ cells without differentiation , we focused on the Wnt pathway which is essential for self -renewal in ESCs . Differentiation of CD133+ cells to CD133 - cells corresponded to down -regulation of Wnt signaling . Pharmacological activation of the Wnt pathway by (2’Z ,3’E ) -6 -Bromoindirubin -3’ -oxime (BIO ) inhibition of GSK -3beta resulted in accelerated differentiation , instead of decreased differentiation , of CD133+ cells . BIO -treated CD133 - cells that were differentiated maintained multipotency while proliferating at similar rates to vehicle -treated CD133+ cells that self -renewed . Therefore , inhibition of GSK -3beta could be a strategy for differentiating CD133+ cells into hematopoietic progenitor cells while maintaining their proliferation capacity . \r \nIn conclusion , this project demonstrated that pathways regulating UCBSC properties are not similar to pathways regulating ESCs properties . Our findings are the first studies that derive UCBSCs properties of self -renewal , differentiation , and multipotency . \r \n & #8195 ;
URI: http : / /hdl .handle .net /2152 .3 /48
Date: 2008-12-17

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Signaling pathways regulating self-renewal, differentiation, and multipotency of CD133+ umbilical cord blood stem cells. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /48 .

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