研究者首次绘制调节成人干细胞生长基因图谱

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最近，美国肯塔基州大学（UK）的Gary Van Zant博士及其研究小组在国际权威科学杂志《自然遗传学》上发表了他们的一项重大成果。他们绘制了一个干细胞基因和它的蛋白产品Laxetin，并且在此工作基础上，进行了鉴定基因自身的调查研究。这是至今为止首次对干细胞基因进行的完全研究。
  这一特殊基因由于能调节体内特别是骨髓内成人干细胞的数目而显得尤为重要。现在它已被鉴定，研究者希望该基因与它的蛋白产品Latexin能够应用于临床。比如，增加进行化疗或者骨髓移植病人的干细胞数量。化疗病人一个大难关是面临治疗后干细胞丧失。这就限制了化疗所能进行的剂量与类型。但是如果Latexin能够用于增加干细胞数量，病人就能够接受更大剂量化疗，并能更快速恢复。在骨髓移植中干细胞数量增加同样有用，在这里需要大量的干细胞来帮助病人从癌症恢复。另外一个Latexin可能的应用是帮助脐带血中干细胞数目，这同样用于血髓移植中移植健康干细胞。目前，脐带血中干细胞移植仅能用于儿童因为脐带血不含有移植给成人所需的足够干细胞数量。
  目前仅在骨髓的干细胞群中检测了Latexin效果。Van Zant说，可能或者很可能在如肝，皮肤，胰腺或大脑组织中的干细胞群能受Latexin的类似影响。这为使用干细胞治疗如由肝病，糖尿病损伤或者中风造成的中枢神经损伤等其他疾病和状况开辟了新的治疗策略。
  研究者同样看到了基因在如白血病和淋巴瘤中正常干细胞转化为癌变干细胞的可能作用。如果基因确实起作用，那么同样可能是新治疗方法的关键。这些发现对于干细胞调节分子机制的深入了解具有作用，这包括一些干细胞如何癌变。这些发现同样有助于科学家发展控制用于治疗的干细胞数目与功能的有效方法，同样为发生在干细胞中年龄相关变化提供了一个较好的解释。





Figure 1. Linkage analysis and Chr3 congenic mouse strains.
(a) Genome-wide linkage analysis for day 35 CAFC frequency from GeneNetwork. The day 35 CAFC numbers per femur for B6, D2 and 26 BXD recombinant strains were derived from previously published data (Supplementary Table 1 online)6, 12 and used for linkage analysis. Three quantitative trait loci (QTL), on chromosomes 3, 5 and 18, respectively, were mapped at a 'suggestive' statistical level of association, in which the likelihood ratio statistic (LRS) values for the corresponding markers (D3Mit5, D5Mit352, D18Mit53) are located between suggestive and significant threshold. The 19 autosomes and X chromosome of the mouse genome are labeled across the top, and some microsatellite markers are listed across the bottom. The positive additive regression coefficient for each QTL indicates that D2 alleles increase the trait, whereas B6 alleles decrease the trait. (b) Schematic illustration of the genomic map of reciprocal Chr3 congenic mouse strains. The B6-derived genomic interval harboring Chr3 QTL (filled bar) was introgressed onto the D2 background (open bar) in congenic D.B Chr3 mice, and vice versa. The consensus congenic interval (cross-hatched bar) extends from 36.5 Mb (19.2 cM 1 cM) to 67.8 Mb (33 cM 1 cM) and includes marker D3Mit5 at 50.4 Mb (25 cM 1 cM), which has the highest linkage to the trait. The total length of chromosome 3 ( 160 Mb) is indicated on the top.





原文出处：

Nature Genetics January 2007 - Vol 39 No 1  advance online publication

The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice
Ying Liang, Michael Jansen, Bruce Aronow, Hartmut Geiger & Gary Van Zant
Published online: 14 January 2007 | doi:10.1038/ng1938
Abstract | Full text | PDF (531K) | Supplementary Information





作者简介：

GARY VAN ZANT, Ph.D.
Professor
Ph.D., New York University, 1973



My laboratory is studying age-related changes in hematopoietic stem cell function. A small population of hematopoietic stem cells in the bone marrow provides large numbers of short-lived, mature blood cells throughout life. What are the effects of aging and replicative stress on the stem cell population? We use mouse genetics to uncover genes affecting the numbers and replication rate of stem cells during aging. We have mapped genetic loci that regulate the physiology of the stem cell population and have found that their genomic map locations coincide with loci affecting mouse lifespan, suggesting that the same genes may be involved. Our current goals are to identify the genes involved and determine their mechanisms of action. Candidate genes at our map locations fit a pattern of encoding components of the DNA repair apparatus and cell cycle checkpoint controls. We have used DNA microarrays and real-time PCR to identify and validate differentially expressed genes in purified stem cells in the search for candidate loci.

Recently a postdoc and graduate students in the lab have begun studies to understand why hematopoietic stem cells undergo a malignant conversion to cause leukemia. Of particular interest are the effects of age and genetic background on carcinogenesis. The effects of replicative stress during aging of the stem cell population is hypothesized to predispose stem cells to genomic instability. Another postdoc, using genetic tools has identified a novel gene with tumor suppressor properties that functions in hematopoietic stem cells and modulates their population size through actions on both apoptosis and stem cell replication. Stem cells interact with stromal cells in the bone marrow and a graduate student has recently discovered a gene whose function in the secretory pathway of stem cells is affected by aging in a way that influences their interaction with their microenvironment.

Selected recent publications:

Geiger, H. & G. Van Zant. The aging of lympho-hematopoietic stem cells. Nat. Immunol. 3:329-333, 2002.

Liang Y & G Van Zant. Genetic control of stem cell properties and stem cells in aging. Curr. Op. Hematol., 10:195-202, 2003.

Van Zant G &Y Liang. The role of stem cells in aging. Exp. Hematol., 31:659-672, 2003.

Meng A, Y Wang, G Van Zant & D Zhou. Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res. 63:5414-5419, 2003.

Geiger H, SJ Szilvassy, P Ragland, G Van Zant. Genetic analysis of progenitor cell mobilization by granulocyte colony-stimulating factor: Verification and mechanisms for loci on murine chromosomes 2 and 11. Exp. Hematol., 32:60-67, 2004.

Bell DR & G Van Zant. Stem cells, aging, and cancer: Inevitabilities and outcomes. Oncogene, 23:7290-7296, 2004.

Liang Y, G Van Zant, SJ Szilvassy. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106:1479-1487, 2005.

Geiger H, GR Rennebeck, G Van Zant. Regulation of hematopoietic stem cell aging in vivo by a a distinct genetic element. Proc. Natl. Acad. Sci., 102:5102-5107, 2005.

Bell DR & G Van Zant. Hematopoietic stem cells, aging, and cancer. In Handbook of the Biology of Aging, pp. 105-123. 6th Edition, EJ Masoro & SN Austad eds, Academic Press, 2006.

Yates, J & G Van Zant. Stem cell exhaustion and aging. In Blood Disorders of the Elderly, L Balducci edl, Cambridge University Press, Cambridge, UK, in press.

Miller A & G Van Zant. Advances in hematopoietic stem cell research through mouse genetics. Curr. Op. Hematol., in press.

Deeg HJ, D Friedman, V Bohr, L Constine, IM Jones, A Sigurdson, G Socie, G Van Zant, Q Wei, P Martin. Transplantation and aging. Biol. Blood Marrow Transplant., in press.

Xing Z, D Daria, K Nattamai, G Van Zant, H Geiger. Hematopoietic stem cell mobilization proficiency increases with age. Blood, in press.