Asymmetric Cell Kinetics Genes: The Key to Expansion of Adult Stem Cells in Culture

A singular challenge in stem cell research today is the expansion and propagation of functional adult stem cells. Unlike embryonic stem cells, which are immortal in culture, adult stem cells are notorious for the difficulty encountered when attempts are made to expand them in culture. One overlooked reason for this difficulty may be the inherent asymmetric cell kinetics of stem cells in postnatal somatic tissues. Senescence is the expected fate of a culture whose growth depends on adult stem cells that divide with asymmetric cell kinetics. Therefore, the bioengineering of strategies to expand adult stem cells in culture requires knowledge of cellular mechanisms that control asymmetric cell kinetics. The properties of several genes recently implicated to function in a cellular pathway(s) that regulates asymmetric cell kinetics are discussed. Understanding the function of these genes in asymmetric cell kinetics mechanisms may be the key that unlocks the adult stem cell expansion problem.

[1]  M. Asashima,et al.  Spemann's influence on Japanese developmental biology. , 2001, The International journal of developmental biology.

[2]  P. Stadler,et al.  Expression of the wild-type p53 antioncogene induces guanine nucleotide-dependent stem cell division kinetics. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[3]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[4]  Yuh Nung Jan,et al.  Asymmetric cell division , 1998, Nature.

[5]  F M Watt,et al.  Out of Eden: stem cells and their niches. , 2000, Science.

[6]  H. Shapiro Ethical Dilemmas and Stem Cell Research , 1999, Science.

[7]  C. Potten,et al.  Epithelial stem cells in vivo , 1988, Journal of Cell Science.

[8]  G. Pellegrini,et al.  Location and Clonal Analysis of Stem Cells and Their Differentiated Progeny in the Human Ocular Surface , 1999, The Journal of cell biology.

[9]  J. Thompson A new lease of life. , 1989, Nursing times.

[10]  A. Spradling,et al.  Stem cells find their niche , 2001, Nature.

[11]  A. Sadikot,et al.  Isolation of multipotent adult stem cells from the dermis of mammalian skin , 2001, Nature Cell Biology.

[12]  E. Furth,et al.  Mutation, cell kinetics, and subpopulations at risk for colon cancer in the United States. , 1998, Mutation research.

[13]  B. Mitchell,et al.  Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene. , 2000, The Journal of clinical investigation.

[14]  G Matioli,et al.  Stochastic stem cell renewal. , 1970, Revue europeenne d'etudes cliniques et biologiques. European journal of clinical and biological research.

[15]  Carlos Cordon-Cardo,et al.  Pten is essential for embryonic development and tumour suppression , 1998, Nature Genetics.

[16]  J. S. Stadler,et al.  A quantitative method for the analysis of mammalian cell proliferation in culture in terms of dividing and non‐dividing cells , 1995, Cell proliferation.

[17]  B. Mitchell,et al.  Inosine-5'-monophosphate dehydrogenase: regulation of expression and role in cellular proliferation and T lymphocyte activation. , 1998, Progress in nucleic acid research and molecular biology.

[18]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[19]  A. Yang,et al.  p63 and p73: p53 mimics, menaces and more , 2000, Nature Reviews Molecular Cell Biology.

[20]  R Montironi,et al.  p63 is a prostate basal cell marker and is required for prostate development. , 2000, The American journal of pathology.

[21]  Y. Liu,et al.  Inosine-5'-monophosphate dehydrogenase is a rate-determining factor for p53-dependent growth regulation. , 1998, Molecular biology of the cell.

[22]  A. Yang,et al.  p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. , 1998, Molecular cell.

[23]  P. Aldhous Can they rebuild us? , 2001, Nature.

[24]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[25]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[26]  J. Sherley,et al.  Breaching the kinetic barrier to in vitro somatic stem cell propagation , 2001, Journal of biomedicine & biotechnology.

[27]  Christopher P. Crum,et al.  p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development , 1999, Nature.

[28]  L. Donehower,et al.  Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours , 1992, Nature.

[29]  G. Dotto,et al.  p21(WAF1/Cip1) functions as a suppressor of malignant skin tumor formation and a determinant of keratinocyte stem-cell potential. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Ponzin,et al.  p63 identifies keratinocyte stem cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  A. Levine,et al.  p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. , 1991, Genes & development.

[32]  David J. Anderson,et al.  Regulatory Mechanisms in Stem Cell Biology , 1997, Cell.

[33]  Elaine Fuchs,et al.  Stem Cells A New Lease on Life , 2000, Cell.

[34]  A. Mclaren,et al.  Ethical and social considerations of stem cell research , 2001, Nature.

[35]  T. Yagi,et al.  Enhanced proliferative potential in culture of cells from p53-deficient mice. , 1993, Oncogene.

[36]  J. Frisén,et al.  Differentiation potential of adult stem cells. , 2001, Current opinion in genetics & development.

[37]  H. Antoniades,et al.  p53 expression during normal tissue regeneration in response to acute cutaneous injury in swine. , 1994, The Journal of clinical investigation.

[38]  S. A. Bohn,et al.  Cellular senescence: ex vivo p53-dependent asymmetric cell kinetics , 2001, Journal of biomedicine & biotechnology.

[39]  J. Sherley Guanine nucleotide biosynthesis is regulated by the cellular p53 concentration. , 1991, The Journal of biological chemistry.

[40]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  U. Lendahl,et al.  Generalized potential of adult neural stem cells. , 2000, Science.

[42]  Neil D. Theise,et al.  Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell , 2001, Cell.

[43]  L. Lajtha Stem cell concepts. , 1979, Nouvelle revue francaise d'hematologie.

[44]  D. van der Kooy,et al.  Separate Proliferation Kinetics of Fibroblast Growth Factor-Responsive and Epidermal Growth Factor-Responsive Neural Stem Cells within the Embryonic Forebrain Germinal Zone , 2000, The Journal of Neuroscience.

[45]  J. Armand,et al.  High incidence of p53 alterations (mutation, deletion, overexpression) in head and neck primary tumors and metastases; absence of correlation with clinical outcome. Frequent protein overexpression in normal epithelium and in early non-invasive lesions. , 1995, Oncogene.

[46]  D. Scadden,et al.  Hematopoietic stem cell quiescence maintained by p21cip1/waf1. , 2000, Science.

[47]  J. Sherley Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture. , 2002, Stem cells.

[48]  H. Blau,et al.  From marrow to brain: expression of neuronal phenotypes in adult mice. , 2000, Science.

[49]  G. Vogel Cell biology. Stem cells: new excitement, persistent questions. , 2000, Science.

[50]  A. Trumpp,et al.  Negative Regulation of Neural Stem/Progenitor Cell Proliferation by the Pten Tumor Suppressor Gene in Vivo , 2001, Science.

[51]  G. Garriga,et al.  Asymmetric cell division: from A to Z. , 1998, Genes & development.

[52]  H. Vogel,et al.  p63 is a p53 homologue required for limb and epidermal morphogenesis , 1999, Nature.

[53]  Peter J. Donovan,et al.  The end of the beginning for pluripotent stem cells , 2001, Nature.

[54]  M. Fiscella,et al.  Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Mckercher,et al.  Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. , 2000, Science.

[56]  C. Doe Spindle Orientation and Asymmetric Localization in Drosophila: Both Inscuteable? , 1996, Cell.

[57]  Stephen J. Elledge,et al.  Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control , 1995, Cell.

[58]  Y. Liu,et al.  Comparison of bax, waf1, and IMP dehydrogenase regulation in response to wild‐type p53 expression under normal growth conditions , 1998, Journal of cellular physiology.

[59]  W. Mars,et al.  Bone marrow as a potential source of hepatic oval cells. , 1999, Science.

[60]  L. Gollahon,et al.  Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome , 1995, Molecular and cellular biology.

[61]  S. Morrison,et al.  Stem cell potential: Can anything make anything? , 2001, Current Biology.

[62]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[63]  A. Gartel,et al.  p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line. , 1996, Experimental cell research.

[64]  J. Moreno A tragic compromise on stem cell derivation , 2001, Journal of Biomedicine and Biotechnology.

[65]  L. Donehower,et al.  In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. , 1993, Oncogene.

[66]  Christopher S Potten,et al.  1 – Stem cells and cellular pedigrees – a conceptual introduction , 1997 .

[67]  David Beach,et al.  p21 is a universal inhibitor of cyclin kinases , 1993, Nature.

[68]  J. Pines,et al.  Cyclin/Cdk-Dependent Initiation of DNA Replication in a Human Cell-Free System , 1997, Cell.

[69]  J. R. Smith,et al.  Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. , 1994, Experimental cell research.

[70]  Wenyi Wei,et al.  Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. , 1997, Science.

[71]  G. Vogel Stem Cells: New Excitement, Persistent Questions , 2000, Science.

[72]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[73]  G. Vogel Can Adult Stem Cells Suffice? , 2001, Science.

[74]  Mary Anne Wheeler,et al.  Stem , 1985 .

[75]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[76]  H. Lin,et al.  Neuroblasts: a model for the asymmetric division of stem cells. , 1997, Trends in genetics : TIG.

[77]  John Cairns,et al.  Mutation selection and the natural history of cancer , 1975, Nature.

[78]  A. I.,et al.  Neural Field Continuum Limits and the Structure–Function Partitioning of Cognitive–Emotional Brain Networks , 2023, Biology.

[79]  B. Rannala,et al.  Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[80]  M. Serrano,et al.  Tumor susceptibility of p21(Waf1/Cip1)-deficient mice. , 2001, Cancer research.

[81]  B O Palsson,et al.  Symmetry of initial cell divisions among primitive hematopoietic progenitors is independent of ontogenic age and regulatory molecules. , 1999, Blood.

[82]  G C Overton,et al.  The genetic program of hematopoietic stem cells. , 2000, Science.

[83]  C. Eaves,et al.  Direct evidence for multiple self-renewal divisions of human in vivo repopulating hematopoietic cells in short-term culture. , 1999, Blood.

[84]  C. Purdie,et al.  Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. , 1994, Oncogene.

[85]  B. Ponder,et al.  Development of the pattern of cell renewal in the crypt-villus unit of chimaeric mouse small intestine. , 1988, Development.

[86]  J. Knoblich,et al.  Mechanisms of asymmetric cell division during animal development. , 1997, Current opinion in cell biology.

[87]  P. Hinds,et al.  Inhibition of p53-mediated growth arrest by overexpression of cyclin-dependent kinases , 1996, Molecular and cellular biology.