生物谷報導：最近，美國肯塔基州大學（UK）的Gary Van Zant博士及其研究小組在國際權威科學雜誌《自然遺傳學》上發表了他們的一項重大成果。他們繪製了一個幹細胞基因和它的蛋白產品Laxetin，並且在此工作基礎上，進行了鑑定基因自身的調查研究。這是至今為止首次對幹細胞基因進行的完全研究。
這一特殊基因由於能調節體內特別是骨髓內成人幹細胞的數目而顯得尤為重要。現在它已被鑑定，研究者希望該基因與它的蛋白產品Latexin能夠應用於臨床。比如，增加進行化療或者骨髓移植病人的幹細胞數量。化療病人一個大難關是面臨治療後幹細胞喪失。這就限制了化療所能進行的劑量與類型。但是如果Latexin能夠用於增加幹細胞數量，病人就能夠接受更大劑量化療，並能更快速恢復。在骨髓移植中幹細胞數量增加同樣有用，在這裡需要大量的幹細胞來幫助病人從癌症恢復。另外一個Latexin可能的應用是幫助臍帶血中幹細胞數目，這同樣用於血髓移植中移植健康幹細胞。目前，臍帶血中幹細胞移植僅能用於兒童因為臍帶血不含有移植給成人所需的足夠幹細胞數量。
目前僅在骨髓的幹細胞群中檢測了Latexin效果。Van Zant說，可能或者很可能在如肝，皮膚，胰腺或大腦組織中的幹細胞群能受Latexin的類似影響。這為使用幹細胞治療如由肝病，糖尿病損傷或者中風造成的中樞神經損傷等其他疾病和狀況開闢了新的治療策略。
研究者同樣看到了基因在如白血病和淋巴瘤中正常幹細胞轉化為癌變幹細胞的可能作用。如果基因確實起作用，那麼同樣可能是新治療方法的關鍵。這些發現對於幹細胞調節分子機制的深入了解具有作用，這包括一些幹細胞如何癌變。這些發現同樣有助於科學家發展控制用於治療的幹細胞數目與功能的有效方法，同樣為發生在幹細胞中年齡相關變化提供了一個較好的解釋。
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 (
原文出處：
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
作者簡介：
GARY VAN ZANT, Ph.D.
Professor
Ph.D.,
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.
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