Sarah Laronde

McMaster University, Hamilton, Ontario, Canada

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Publications (4)59.92 Total impact

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    ABSTRACT: Graphical Abstract Highlights d Human blood can be directly converted to tripotent iNPCs with a single factor d BD-iNPCs uniquely differentiate to neurons with properties of both CNS and PNS d Conversion process toward iNPCs from blood differs from fibroblasts d Nociceptive neurons recapitulate chemo-induced neuropathy in a screening format Correspondence mbhatia@mcmaster.ca In Brief Using OCT-4-induced direct reprogramming, Lee et al. convert human blood to neural progenitors with both CNS and PNS developmental capacity. This fate alternation is distinct from fibroblasts that are primed for neural potential. Furthermore, human sensory neurons derived from blood phenocopy chemo-induced neuropathy in formats suitable for drug screening.
    Cell Reports 07/2015; 11(9):1-10. DOI:10.1016/j.celrep.2015.04.056 · 8.36 Impact Factor
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    ABSTRACT: Current treatments that utilize hematopoietic progenitor cell (HPC) transplantation in AML patients substantially reduce the risk of relapse, but are limited by the availability of immune compatible healthy HPCs. Although cellular reprogramming has the potential to provide a novel autologous source of HPCs for transplantation, the applicability of this technology toward the derivation of healthy autologous hematopoietic cells devoid of patient-specific leukemic aberrations from AML patients must first be evaluated. Here we report the generation of human AML patient-specific hematopoietic progenitors that are capable of normal in vitro differentiation to myeloid lineages and are devoid of leukemia-associated aberration found in matched patient bone marrow. Skin fibroblasts were obtained from AML patients whose leukemic cells possessed a distinct, leukemia-associated aberration, and used to create AML patient-specific induced pluripotent stem cells (iPSCs). Through hematopoietic differentiation of AML patient iPSCs, coupled with cytogenetic interrogation, we reveal that AML patient-specific HPCs possess normal progenitor capacity and are devoid of leukemia-associated mutations. Importantly, in rare patient skin samples that give rise to mosaic fibroblast cultures that continue to carry leukemia-associated mutations; healthy hematopoietic progenitors can also be generated via reprogramming selection. Our findings provide the proof of principle that cellular reprogramming can be applied on a personalized basis to generate healthy HPCs from AML patients, and should further motivate advances toward creating transplantable hematopoietic stem cells for autologous AML therapy. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 03/2015; 33(6). DOI:10.1002/stem.1994 · 7.70 Impact Factor
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    ABSTRACT: Human-induced pluripotent stem cells (hiPSCs) provide an invaluable source for regenerative medicine, but are limited by proficient lineage-specific differentiation. Here we reveal that hiPSCs derived from human fibroblasts (Fibs) versus human cord blood (CB) exhibit indistinguishable pluripotency, but harbour biased propensities for differentiation. Genes associated with germ layer specification were identical in Fib- or CB-derived iPSCs, whereas lineage-specific marks emerge upon differentiation induction of hiPSCs that were correlated to the cell of origin. Differentiation propensities come at the expense of other lineages and cannot be overcome with stimuli for alternative cell fates. Although incomplete DNA methylation and distinct histone modifications of lineage-specific loci correlate to lineage-specific transcriptome priming, transitioning hiPSCs into naive state of pluripotency removes iPSC-memorized transcriptome. Upon re-entry to the primed state, transcriptome memory is restored, indicating a human-specific phenomenon whereby lineage gated developmental potential is not permanently erased, but can be modulated by the pluripotent state.
    Nature Communications 12/2014; 5:5605. DOI:10.1038/ncomms6605 · 10.74 Impact Factor
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    ABSTRACT: Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.
    Cell 05/2012; 149(6):1284-97. DOI:10.1016/j.cell.2012.03.049 · 33.12 Impact Factor

Publication Stats

102 Citations
59.92 Total Impact Points

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Institutions

  • 2012–2015
    • McMaster University
      • • Michael G. DeGroote School of Medicine
      • • Stem Cell and Cancer Research Institute
      Hamilton, Ontario, Canada