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Clayton South, Australia

Ellis S.L.,Peter MacCallum Cancer Center | Ellis S.L.,Australian Stem Cell Center | Ellis S.L.,University of Melbourne | Grassinger J.,University of Regensburg | And 7 more authors.
Blood | Year: 2011

A large body of evidence suggests hemopoietic stem cells (HSCs) exist in an endosteal niche close to bone, whereas others suggest that the HSC niche is intimately associated with vasculature. In this study, we show that transplanted hemopoietic stem and progenitor cells (HSPCs) home preferentially to the trabecular-rich metaphysis of the femurs in nonablated mice at all time points from 15 minutes to 15 hours after transplantation. Within this region, they exist in an endosteal niche in close association with blood vessels. The preferential homing of HSPCs to the metaphysis occurs rapidly after transplantation, suggesting that blood vessels within this region may express a unique repertoire of endothelial adhesive molecules. One candidate is hyaluronan (HA), which is highly expressed on the blood vessel endothelium in the metaphysis. Analysis of the early stages of homing and the spatial distribution of transplanted HSPCs at the single-cell level in mice devoid of Has3-synthesized HA, provides evidence for a previously undescribed role for HA expressed on endothelial cells in directing the homing of HSPCs to the metaphysis. © 2011 by The American Society of Hematology.

Chung T.-L.,University of Queensland | Chung T.-L.,Australian Stem Cell Center | Chung T.-L.,Monash Institute of Medical Research | Brena R.M.,University of Southern California | And 6 more authors.
Stem Cells | Year: 2010

Vitamin C (ascorbate) is a widely used medium supplement in embryonic stem cell culture. Here, we show that ascorbate causes widespread, consistent, and remarkably specific DNA demethylation of 1,847 genes in human embryonic stem cells (hESCs), including important stem cell genes, with a clear bias toward demethylation at CpG island boundaries. We show that a subset of these DNA demethylated genes displays concomitant gene expression changes and that the position of the demethylated CpGs relative to the transcription start site is correlated to such changes. We further show that the ascorbate-demethylated gene set not only overlaps with gene sets that have bivalent marks, but also with the gene sets that are demethylated during differentiation of hESCs and during reprogramming of fibroblasts to induced pluritotent stem cells (iPSCs). Our data thus identify a novel link between ascorbate-mediated signaling and specific epigenetic changes in hESCs that might impact on pluripotency and reprogramming pathways. © AlphaMed Press.

Sambrook J.,Australian Stem Cell Center
Australasian Biotechnology | Year: 2010

Stem cell science has captured the imagination of the public like no other scientific field in recent times. A mix of hype and breathtaking scientific breakthroughs has combined to create hope and expectation that it may one day provide a cure for currently incurable diseases and injuries. However, as researchers and regulators move forward cautiously, the public is becoming impatient.

Teisanu R.M.,Duke University | Chen H.,Duke University | Matsumoto K.,Duke University | McQualter J.L.,Australian Stem Cell Center | And 6 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2011

Air spaces of the mammalian lung are lined by a specialized epithelium that is maintained by endogenous progenitor cells. Within bronchioles, the abundance and distribution of progenitor cells that contribute to epithelial homeostasis change as a function of maintenance versus repair. It is unclear whether functionally distinct progenitor pools or a single progenitor cell type maintain the epithelium and how the behavior is regulated in normal or disease states. To address these questions, we applied fractionation methods for the enrichment of distal airway progenitors. We show that bronchiolar progenitor cells can be subdivided into two functionally distinct populations that differ in their susceptibility to injury and contribution to repair. The proliferative capacity of these progenitors is confirmed in a novel in vitro assay. We show that both populations give rise to colonies with a similar dependence on stromal cell interactions and regulation by TGF-β. These findings provide additional insights into mechanisms of epithelial remodeling in the setting of chronic lung disease and offer hope that pharmacologic interventions may be developed to mitigate tissue remodeling.

Chung T.-L.,University of Queensland | Chung T.-L.,Australian Stem Cell Center | Chung T.-L.,Monash Institute of Medical Research | Turner J.P.,University of Queensland | And 6 more authors.
Stem Cells | Year: 2010

Human embryonic stem cells (hESCs) and induced pluripotent stem cells have the ability to adapt to various culture conditions. Phenotypic and epigenetic changes brought about by the culture conditions can, however, have significant impacts on their use in research and in clinical applications. Here, we show that diploid hESCs start to express CD30, a biomarker for malignant cells in Hodgkin's disease and embryonal carcinoma cells, when cultured in knockout serum replacement (KOSR)-based medium, but not in fetal calf serum containing medium. We identify the commonly used medium additive, ascorbate, as the sole medium component in KOSR responsible for CD30 induction. Our data show that this epigenetic activation of CD30 expression in hESCs by ascorbate occurs through a dramatic loss of DNA methylation of a CpG island in the CD30 promoter. Analysis of the pheno-type and transcriptome of hESCs that overexpress the CD30 signaling domain reveals that CD30 signaling leads to inhibition of apoptosis, enhanced single-cell growth, and transcriptome changes that are associated with cell signaling, lipid metabolism, and tissue development. Collectively, our data show that hESC culture media that contain ascorbate trigger CD30 expression through an epigenetic mechanism and that this provides a survival advantage and transcriptome changes that may help adapt hESCs to in vitro culture conditions. © AlphaMed Press.

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