CSHL Press News

Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt Signaling is Necessary to Promote Primitive Hematopoietic Stem Cell Self-Renewal and Expansion

John M Perry, Xi C He, Justin C Grindley, Jeffrey S Haug, Sheng Ding, and Linheng Li

The expansion of stem cell populations depends upon a dynamic balance between active proliferation and the suppression of both differentiation and apoptosis. In this paper, Perry et al. investigated how the Wnt/β-catenin and PTEN/PI3K/Akt pathways cooperate in hematopoietic stem cells (HSC) to regulate self-renewal and expansion. The authors used a compound mutant mouse model that coupled the loss of PTEN (and resultant activation of PI3K/Akt signaling) with β-catenin activation specifically in HSC stem and progenitor cells. They found that activation of the Wnt/β-catenin pathway, alone, blocked overall differentiation but also resulted in apoptosis, while activation of the PI3K/Akt pathway, alone, resulted in increased differentiation but also facilitated cell survival.  However, the combined activation of both pathways allowed for expansion of HSCs by mutually blocking both differentiation and apoptosis in proliferating cells.  This demonstrated that both pathways function cooperatively to promote HSC self-renewal. Furthermore, the reversible pharmacological activation of both pathways in culture enabled the authors to expand primitive HSCs so as to support blood formation in mice through three sequential transplantation experiments.  Dr. Li commented that “if similar results can be achieved using humanHSCs from sources such as umbilical cord blood, this work is expected to have substantial clinical impact.” 

Integrative Annotation of Human Large Intergenic Non-Coding RNAs Reveals Global Properties and Specific Subclasses

Moran N Cabili, Cole Trapnell, Loyal Goff, Magdalena Koziol, Barbara Tazon-Vega, Aviv Regev, and John L Rinn

A large part of the human genome codes for noncoding RNA (ncRNA). Here, Cabili et al. present the first comprehensive map of large intergenic noncoding RNAs (lincRNAs), providing insight into the characteristics and properties of these RNAs. Cabili et al. developed an integrative and universally applicable computational method to comprehensively annotate lincRNA transcript structures. When the authors applied their system to the human genome, they identified 8000 lincRNAs – over 5000 of which were undiscovered – that they were then able to further characterize based on various properties, including sequence, structural, transcriptional, and orthological features.  Their analysis revealed that lincRNAs exhibit tissue-specific expression patterns, and are often associated with disease-susceptibility loci. Dr. Rinn is confident that “this map of non-codarnia allows identification of these mysterious molecules and provides a systematic approach for hypothesis-driven experiments to uncover the functional roles of lincRNAs.”

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