Cell Cycle Regulation in Bypassing Senescence

To proliferate, cells transverse the cell cycle in several, discrete, well-controlled phases and any break down in this regulation may result into uncontrolled growth. The first is the G1 phase, where the cells commit to enter the cell cycle and prepare to duplicate their DNA in S phase. After S phase, cells enter the G2 phase, where DNA repair may take place along with preparation for mitosis in M phase. In the M phase, chromatids and daughter cells separate, after which, the cells can enter G1 or G0, a quiescent phase. Entry into each phase of the cell cycle is carefully regulated by receptor collectives, termed cell cycle checkpoints. At this stage, the cell is ready for responding to these external stimuli, communicated through a cascade of intracellular phosphorylations, by up-regulating expression of the cyclins and cyclin dependent kinases (CDKs) leading to cell cycle regulation. The Cyclin is the regulatory unit and CDK is its catalytic partner. Cyclins, with their bound and activated CDKs, function during distinct stages of the cell cycle.

Stem cells are defined by both their ability to make more replicas of themselves, a property known as "self renewal", and their ability to produce differentiated cells. It is more or less well established that asymmetric cell division is a defining characteristic of stem cells that enable them to simultaneously perpetuate themselves in culture (Morrison and Kimble, 2006). However, to understand self renewal, it is not sufficient merely to delineate how stem cell proliferation is controlled, because not all cell divisions involve self renewal. Are there specific signals that exert a combined effect on cell cycle regulation and maintenance of stem cell state? Or are proliferation and maintenance of stem cell state regulated independently by distinct signals? If yes, what are the appropriate downstream regulators starting from activation of a specific pathway? All these issues are critical as answers to these questions may provide important clues about how to induce ESCs into different lineages in a controlled manner in culture, an essential element in their therapeutic application.

Table 1. Expression of pluripotency related genes in hESCs

Category

Gene Symbol

Description

ReliCellĀ®hES1

Oct-3/4

POU domain, class 5, transcription factor 1

240

Nanog

NK2-family homeobox gene

21

DNMT

DNA methyl transferase 3ft

42

Pluripotency

UTF1

Undifferentiated embryonic stem cell

149

transcriptional factor 1

TDGF1

Teratocarcinoma-derived growth factor 1

1722

Rex

Zinc figure protein 42

530

Table 1. (Continued)

Category

Gene Symbol

Description

ReliCellĀ®hES1

Lefty A

left-right determination, factor A

1136

Lefty B

left-right determination, factor B

2635

Dppa5

Developmental pluripotency associated 5

269

TERF1

Telomeric repeat binding factor 1

1111

TERF2

Telomeric repeat binding factor 2

735

CX43

Gap junction molecule, Connexin 43

1589

Lin28

Lin-28 homolog (C. elegans)

2540

Podxl

Podocalyxin-like transcript variant

1063

Gal

Galanin

1158

BMP3B

Bone morphogenetic protein 3B

254

Wnt3A

wingless-type MMTV integration site family, member 3A

296

Wnt4

wingless-type MMTV integration site family, member 4

50

LIFR

Leukemia inhibitory factor-receptor

ND

gp130

Signal transducer and activator of transcription 3, glycoprotein 130

ND

FoxD3

forkhead box D3

21

ND: Not Detected; values mentioned in column 4 are arbitrary intensity units as detected by Illumina bead array system (Pal et al., 2007).

ND: Not Detected; values mentioned in column 4 are arbitrary intensity units as detected by Illumina bead array system (Pal et al., 2007).

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