Transcriptional Regulation of Stem Cell Self-Renewal.

[摘要] Self-renewal is a defining feature that distinguishes stem cells from transiently amplifying progenitors. Regulation of stem cell self-renewal involves precise control of cell cycle progression, suppression of premature differentiation, as well as maintenance of stem cell genomic integrity. The polycomb group protein Bmi-1 is essential for the postnatal self-renewal of mouse neural stem cells. We show that the depletion of neural stem cells in the absence of Bmi-1 is partially due to the derepression of two cell cycle inhibitors, p16Ink4a and p19Arf. Deletion of Ink4a and Arf from Bmi-1 deficient mice is sufficient to partially rescue the self-renewal defects of neural stem cells, indicating Bmi-1 regulates adult neural stem cell self-renewal mainly, but not exclusively by repressing the expression of Ink4a and Arf. Conversely, overexpression of Bmi-1 is sufficient to enhance the self-renewal potential of CNS neural stem cells in vitro by suppressing culture-induced Ink4a and Arf expression, but has little effect on stem cell number or SVZ proliferation in vivo, where Ink4a and Arf are not normally expressed. Together, our data demonstrate that stem cell self-renewal capacity is modulated by factors affecting their cell cycle progression.The Sry-related HMG box transcription factor Sox17 is specifically expressed by fetal, but not adult, hematopoietic stem cells (HSCs), and is essential for their maintenance. We demonstrate that Sox17 overexpression is sufficient to confer adult hematopoietic progenitors with certain fetal characteristics, and bias adult hematopoiesis to resemble fetal hematopoiesis. This is achieved at least partially by upregulating fetal HSC-specific gene expression, and suppressing differentiation-associated genes. Sox17 may therefore maintain fetal HSC identity by repressing differentiation or lineage commitment.The immortal strand hypothesis has been proposed as a mechanism to protect the genomic integrity of stem cells by asymmetrically segregating old and newly synthesized chromosomes during cell division. Using HSCs as a model system, we demonstrate that asymmetric chromosome segregation does not occur at a significant frequency in HSCs in vivo or in culture. Therefore ;;immortal strand” segregation cannot be a universal mechanism protecting stem cells from accumulating genetic mutations.

[发布机构] University of Michigan

[效力级别] Self-renewal

[关键词] Stem Cells;Self-renewal;Bmi-1;Sox17;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology