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Sean J Morrison - One of the best experts on this subject based on the ideXlab platform.

  • oestrogen increases haematopoietic Stem Cell self renewal in females and during pregnancy
    Nature, 2014
    Co-Authors: Daisuke Nakada, Hideyuki Oguro, Boaz P Levi, Nicole Ryan, Ayumi Kitano, Yusuke Saitoh, Makiko Takeichi, George R Wendt, Sean J Morrison
    Abstract:

    Haematopoietic Stem Cells are found to be regulated differently in male and female mice — haematopoietic Stem Cells in females divide more frequently than in males in response to oestrogen and this difference depends on the ovaries but not the testes; using a genetic approach, it is shown that the effect is dependent on expression of oestrogen receptor-α (ERα) in Stem Cells. The extent to which Stem Cells are regulated by long-range signals versus local signals within tissues is a fundamental question in Stem-Cell biology. Much recent research has focused on how the Stem-Cell niche responds to local signals within tissues. But in conditions such as starvation or pregnancy it is likely that syStemic signals will modulate Stem-Cell function in multiple tissues, and this study demonstrates a long-range effect of oestrogen on haematopoietic Stem Cells (HSCs) in pregnant mice. Using a genetic approach, the authors show that HSC stimulation, which would help the mother to meet increased haematopoietic demands, is dependent on expression of the oestrogen receptor (ERα). Hormonal levels differ in males and females but so too do the HSC Cells — Stem Cells in female mice divide significantly more frequently than those in male mice in response to oestrogen. Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain Stem Cells that are directly or indirectly regulated by sex hormones1,2,3,4,5,6. An important question is whether Stem Cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences. The terminal differentiation and function of some haematopoietic Cells are regulated by sex hormones7,8,9,10, but haematopoietic Stem-Cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic Stem Cells exhibit sex differences in Cell-cycle regulation by oestrogen. Haematopoietic Stem Cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic Stem-Cell division in males and females. Oestrogen levels increased during pregnancy, increasing haematopoietic Stem-Cell division, haematopoietic Stem-Cell frequency, Cellularity, and erythropoiesis in the spleen. Haematopoietic Stem Cells expressed high levels of oestrogen receptor-α (ERα). Conditional deletion of ERα from haematopoietic Stem Cells reduced haematopoietic Stem-Cell division in female, but not male, mice and attenuated the increases in haematopoietic Stem-Cell division, haematopoietic Stem-Cell frequency, and erythropoiesis during pregnancy. Oestrogen/ERα signalling promotes haematopoietic Stem-Cell Self-Renewal, expanding splenic haematopoietic Stem Cells and erythropoiesis during pregnancy.

  • temporal changes in pten and mtorc2 regulation of hematopoietic Stem Cell self renewal and leukemia suppression
    Cell Stem Cell, 2012
    Co-Authors: Jeffrey A Magee, Tsuneo Ikenoue, Daisuke Nakada, Kunliang Guan, Sean J Morrison
    Abstract:

    Pten deletion from adult mouse hematopoietic Cells activates the PI3-kinase pathway, inducing hematopoietic Stem Cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult Cells are not required by neonatal Cells. Developmental changes in key signaling pathways therefore confer temporal changes upon Stem Cell Self-Renewal and tumor suppressor mechanisms.

  • mechanisms of Stem Cell self renewal
    Annual Review of Cell and Developmental Biology, 2009
    Co-Authors: Shenghui He, Daisuke Nakada, Sean J Morrison
    Abstract:

    Self-Renewal is the process by which Stem Cells divide to make more Stem Cells, perpetuating the Stem Cell pool throughout life. Self-Renewal is division with maintenance of the undifferentiated state. This requires Cell cycle control and often maintenance of multipotency or pluripotency, depending on the Stem Cell. Self-Renewal programs involve networks that balance proto-oncogenes (promoting Self-Renewal), gate-keeping tumor suppressors (limiting Self-Renewal), and care-taking tumor suppressors (maintaining genomic integrity). These Cell-intrinsic mechanisms are regulated by Cell-extrinsic signals from the niche, the microenvironment that maintains Stem Cells and regulates their function in tissues. In response to changing tissue demands, Stem Cells undergo changes in Cell cycle status and developmental potential over time, requiring different Self-Renewal programs at different stages of life. Reduced Stem Cell function and tissue regenerative capacity during aging are caused by changes in Self-Renewal ...

  • hmga2 promotes neural Stem Cell self renewal in young but not old mice by reducing p16ink4a and p19arf expression
    Cell, 2008
    Co-Authors: Jinsuke Nishino, Injune Kim, Kiran Chada, Sean J Morrison
    Abstract:

    Stem Cells persist throughout life in diverse tissues by undergoing self-renewing divisions. Self-Renewal capacity declines with age, partly because of increasing expression of the tumor suppressor p16(Ink4a). We discovered that the Hmga2 transcriptional regulator is highly expressed in fetal neural Stem Cells but that expression declines with age. This decrease is partly caused by the increasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice show reduced Stem Cell numbers and Self-Renewal throughout the central and peripheral nervous syStems of fetal and young-adult mice but not old-adult mice. Furthermore, p16(Ink4a) and p19(Arf) expression were increased in Hmga2-deficient fetal and young-adult Stem Cells, and deletion of p16(Ink4a) and/or p19(Arf) partially restored Self-Renewal capacity. let-7b overexpression reduced Hmga2 and increased p16(Ink4a)/p19(Arf) expression. Hmga2 thus promotes fetal and young-adult Stem Cell Self-Renewal by decreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural Stem Cell function.

  • bmi 1 promotes neural Stem Cell self renewal and neural development but not mouse growth and survival by repressing the p16ink4a and p19arf senescence pathways
    Genes & Development, 2005
    Co-Authors: Anna V. Molofsky, Sean J Morrison, Shenghui He, Mohammad Bydon, Ricardo Pardal
    Abstract:

    Bmi-1 is required for the post-natal maintenance of Stem Cells in multiple tissues including the central nervous syStem (CNS) and peripheral nervous syStem (PNS). Deletion of Ink4a or Arf from Bmi-1-/- mice partially rescued Stem Cell Self-Renewal and Stem Cell frequency in the CNS and PNS, as well as forebrain proliferation and gut neurogenesis. Arf deficiency, but not Ink4a deficiency, partially rescued cerebellum development, demonstrating regional differences in the sensitivity of progenitors to p16Ink4a and p19Arf. Deletion of both Ink4a and Arf did not affect the growth or survival of Bmi-1-/- mice or completely rescue neural development. Bmi-1 thus prevents the premature senescence of neural Stem Cells by repressing Ink4a and Arf, but additional pathways must also function downstream of Bmi-1.

Juan Carlos Izpisua Belmonte - One of the best experts on this subject based on the ideXlab platform.

  • albumin associated lipids regulate human embryonic Stem Cell self renewal
    PLOS ONE, 2008
    Co-Authors: Francesc R Garciagonzalo, Juan Carlos Izpisua Belmonte
    Abstract:

    BACKGROUND: Although human embryonic Stem Cells (hESCs) hold great promise as a source of differentiated Cells to treat several human diseases, many obstacles still need to be surmounted before this can become a reality. First among these, a robust chemically-defined syStem to expand hESCs in culture is still unavailable despite recent advances in the understanding of factors controlling hESC Self-Renewal. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we attempted to find new molecules that stimulate long term hESC Self-Renewal. In order to do this, we started from the observation that a commercially available serum replacement product has a strong positive effect on the expansion of undifferentiated hESCs when added to a previously reported chemically-defined medium. Subsequent experiments demonstrated that the active ingredient within the serum replacement is lipid-rich albumin. Furthermore, we show that this activity is trypsin-resistant, strongly suggesting that lipids and not albumin are responsible for the effect. Consistent with this, lipid-poor albumin shows no detectable activity. Finally, we identified the major lipids bound to the lipid-rich albumin and tested several lipid candidates for the effect. CONCLUSIONS/SIGNIFICANCE: Our discovery of the role played by albumin-associated lipids in stimulating hESC Self-Renewal constitutes a significant advance in the knowledge of how hESC pluripotency is maintained by extraCellular factors and has important applications in the development of increasingly chemically defined hESC culture syStems.

  • Albumin-associated lipids regulate human embryonic Stem Cell Self-Renewal.
    PloS one, 2008
    Co-Authors: Francesc R. Garcia-gonzalo, Juan Carlos Izpisua Belmonte
    Abstract:

    Background Although human embryonic Stem Cells (hESCs) hold great promise as a source of differentiated Cells to treat several human diseases, many obstacles still need to be surmounted before this can become a reality. First among these, a robust chemically-defined syStem to expand hESCs in culture is still unavailable despite recent advances in the understanding of factors controlling hESC Self-Renewal. Methodology/Principal Findings In this study, we attempted to find new molecules that stimulate long term hESC Self-Renewal. In order to do this, we started from the observation that a commercially available serum replacement product has a strong positive effect on the expansion of undifferentiated hESCs when added to a previously reported chemically-defined medium. Subsequent experiments demonstrated that the active ingredient within the serum replacement is lipid-rich albumin. Furthermore, we show that this activity is trypsin-resistant, strongly suggesting that lipids and not albumin are responsible for the effect. Consistent with this, lipid-poor albumin shows no detectable activity. Finally, we identified the major lipids bound to the lipid-rich albumin and tested several lipid candidates for the effect. Conclusions/Significance Our discovery of the role played by albumin-associated lipids in stimulating hESC Self-Renewal constitutes a significant advance in the knowledge of how hESC pluripotency is maintained by extraCellular factors and has important applications in the development of increasingly chemically defined hESC culture syStems.

Jeffrey L Wrana - One of the best experts on this subject based on the ideXlab platform.

Phablo Abreu - One of the best experts on this subject based on the ideXlab platform.

  • bioenergetics mechanisms regulating muscle Stem Cell self renewal commitment and function
    Biomedicine & Pharmacotherapy, 2018
    Co-Authors: Phablo Abreu
    Abstract:

    Muscle Stem Cells or satellite Cells are crucial for muscle maintenance and repair. These Cells are mitotically quiescent and uniformly express the transcription factor Pax7, intermittently entering the Cell cycle to give rise to daughter myogenic precursors Cells and fuse with neighboring myofibers or self-renew, replenishing the Stem Cell pool in adult skeletal muscle. Pivotal roles of muscle Stem Cells in muscle repair have been uncovered, but it still remains unclear how muscle Stem Cell Self-Renewal is molecularly regulated and how muscle Stem Cells maintain muscle tissue homeostasis. Defects in muscle Stem Cell regulation to maintain/return to quiescence and self-renew are observed in degenerative conditions such as aging and neuromuscular disease. Recent works has suggested the existence of metabolic regulation and mitochondrial alterations in muscle Stem Cells, influencing the Self-Renewal commitment and function. Here I present a brief overview of recent understanding of how metabolic reprogramming governs Self-Renewal commitment, which is essential for conservation of muscle satellite Cell pools throughout life, as well as the implications for regenerative medicine.

Jiwang Zhang - One of the best experts on this subject based on the ideXlab platform.

  • bmp signaling and Stem Cell regulation
    Developmental Biology, 2005
    Co-Authors: Jiwang Zhang
    Abstract:

    Stem Cells play an essential role in Cellular specialization and pattern formation during embryogenesis and in tissue regeneration in adults. This is mainly due to a Stem Cell's ability to replenish itself (Self-Renewal) and, at the same time, produce differentiated progeny. Realization of these special Stem Cell features has changed the prospective of the field. However, regulation of Stem Cell Self-Renewal and maintenance of its potentiality require a complicated regulatory network of both extraCellular cues and intrinsic programs. Understanding how signaling regulates Stem Cell behavior will shed light on the molecular mechanisms underlying Stem Cell Self-Renewal. In this review, we focus on comparing the progress of recent research regarding the roles of the BMP signaling pathway in different Stem Cell syStems, including embryonic Stem Cells, germline Stem Cells, hematopoietic Stem Cells, and intestinal Stem Cells. We hope this comparison, together with a brief look at other signaling pathways, will bring a more balanced view of BMP signaling in regulation of Stem Cell properties, and further point to a general principle that Self-Renewal of Stem Cells may require a combination of maintenance of proliferation potential, inhibition of apoptosis, and blocking of differentiation.

  • bmp signaling inhibits intestinal Stem Cell self renewal through suppression of wnt β catenin signaling
    Nature Genetics, 2004
    Co-Authors: Xi C He, Jiwang Zhang, Weigang Tong, Ossama Tawfik, Jason T Ross, David H Scoville, Qiang Tian, Xin Zeng, Xi He
    Abstract:

    In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome1, juvenile intestinal polyposis2 and Cowden disease3, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways4,5. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the Stem and progenitor Cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of Stem Cell Self-Renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase–Akt, mediates the convergence of the BMP and Wnt pathways on control of β-catenin. Thus, BMP signaling may control the duplication of intestinal Stem Cells, thereby preventing crypt fission and the subsequent increase in crypt number.

  • bmp signaling inhibits intestinal Stem Cell self renewal through suppression of wnt β catenin signaling
    Nature Genetics, 2004
    Co-Authors: Jiwang Zhang, Weigang Tong, Ossama Tawfik, Jason T Ross, David H Scoville, Qiang Tian, Xin Zeng, Leanne M Wiedemann
    Abstract:

    In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the Stem and progenitor Cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of Stem Cell Self-Renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal Stem Cells, thereby preventing crypt fission and the subsequent increase in crypt number.