Kyle R. Salci

McMaster University

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Mickie Bhatia

Wayne State University

Zoya Shapovalova

McMaster University

Aline Fiebig‐Comyn

McMaster University

Luca Orlando

FIT Consulting (Italy)

Ryan R. Mitchell

McMaster University

Brendan A.S. McIntyre

Children's Hospital of Philadelphia

Allison L. Boyd

McMaster University

Tony Collins

De Montfort University

Brian Leber

McMaster University

Ronan Foley

Juravinski Hospital

Cooperative Institutions

McMaster University

Population Health Research Institute

Cancer Research Institute

Cancer Research Institute of the Slovak Academy of Sciences

Hamilton Health Sciences

Leukemia & Lymphoma Society of Canada

Juravinski Hospital

Juravinski Cancer Centre

University of Toronto

McMaster University Medical Centre

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Acquisition of pluripotency through continued environmental influence on OCT4-induced plastic human fibroblasts

Stem Cell Research (2015)

Kyle R. Salci Jung Bok Lee Ryan R. Mitchell Luca Orlando Aline Fiebig‐Comyn

The combination of OCT4 expression and short-term exposure to reprogramming media induces a state of transcriptional plasticity in human fibroblasts, capable of responding to changes in the extracellular environment that facilitate direct cell fate conversion toward lineage specific progenitors. Here we reveal that continued exposure of OCT4-induced plastic human fibroblasts to reprogramming media (RM) is sufficient to induce pluripotency. OCT4-derived induced pluripotent stem cell (iPSC(OCT4)) colonies emerged after prolonged culture in RM, and formed independently of lineage specific progenitors. Human iPSC(OCT4) are morphologically indistinguishable from conventionally derived iPSCs and express core proteins involved in maintenance of pluripotency. iPSC(OCT4) display in vivo functional pluripotency as measured by teratoma formation consisting of the three germ layers, and are capable of targeted in vitro differentiation. Our study indicates that acquisition of pluripotency is one of multiple cell fate choices that can be facilitated through environmental stimulation of OCT4-induced plasticity, and suggests the role of other reprogramming factors to induce pluripotency can be substituted by prolonged culture of plastic fibroblasts.

Reprogramming

Germ layer

Cell fate determination

10.1016/j.scr.2015.06.006

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Citations (6)

Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche

Nature Cell Biology (2017)

Allison L. Boyd Jennifer Reid Kyle R. Salci Lili Aslostovar Yannick D. Benoit

10.1038/ncb3625

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Citations (176)

Nonhematopoietic cells represent a more rational target of in vivo hedgehog signaling affecting normal or acute myeloid leukemia progenitors

Experimental Hematology (2013)

Allison L. Boyd Kyle R. Salci Zoya Shapovalova Brendan A.S. McIntyre Mickie Bhatia

Progenitor

10.1016/j.exphem.2013.05.287

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Citations (21)

Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations

Stem Cells (2017)

Jong‐Hee Lee Kyle R. Salci Jennifer Reid Luca Orlando Borko Tanasijevic

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095-2102.

Reprogramming

10.1002/stem.2655

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Citations (28)

Sam68 Allows Selective Targeting of Human Cancer Stem Cells

Cell chemical biology (2017)

Yannick D. Benoit Ryan R. Mitchell Ruth M. Risueño Luca Orlando Borko Tanasijevic

10.1016/j.chembiol.2017.05.026

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Citations (44)

Expansive Generation of Functional Airway Epithelium From Human Embryonic Stem Cells

Stem Cells Translational Medicine (2013)

Brendan A.S. McIntyre Cantas Alev Rami Mechael Kyle R. Salci Jung Bok Lee

Production of human embryonic stem cell (hESC)-derived lung progenitors has broad applicability for drug screening and cell therapy; however, this is complicated by limitations in demarcating phenotypic changes with functional validation of airway cell types. In this paper, we reveal the potential of hESCs to produce multipotent lung progenitors using a combined growth factor and physical culture approach, guided by the use of novel markers LIFRα and NRP1. Lung specification of hESCs was achieved by priming differentiation via matrix-specific support, followed by air-liquid interface to allow generation of lung progenitors capable of in vitro maturation into airway epithelial cell types, resulting in functional characteristics such as secretion of pulmonary surfactant, ciliation, polarization, and acquisition of innate immune activity. This approach provided a robust expansion of lung progenitors, allowing in vivo assessment, which demonstrated that only fully differentiated hESC-derived airway cells were retained in the distal airway, where they aided in physiological recovery in immunocompromised mice receiving airway injury. Our study provides a basis for translational applications of hESCs for lung diseases.

10.5966/sctm.2013-0119

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Citations (30)

Foundational concepts of cell fate conversion to the hematopoietic lineage

Current Opinion in Genetics & Development (2013)

Kyle R. Salci Brendan A.S. McIntyre Mickie Bhatia

Reprogramming

Lineage (genetic)

10.1016/j.gde.2013.04.007

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Citations (3)

Cellular reprogramming of human acute myeloid leukemia patient somatic cells

Kyle R. Salci

Reprogramming

Source

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Citations (0)

Cellular Reprogramming Allows Generation of Autologous Hematopoietic Progenitors From AML Patients That Are Devoid of Patient-Specific Genomic Aberrations

Stem Cells (2015)

Kyle R. Salci Jong‐Hee Lee Sarah Laronde Steve Dingwall Rahul Kushwah

Current treatments that use hematopoietic progenitor cell (HPC) transplantation in acute myeloid leukemia (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.

Reprogramming

10.1002/stem.1994

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Citations (16)

Derivation of human induced pluripotent stem cells through continued exposure of OCT4-induced plastic human fibroblasts to reprogramming media

Stem Cell Research (2015)

Kyle R. Salci Jung Bok Lee Ryan R. Mitchell Luca Orlando Aline Fiebig‐Comyn

The combination of OCT4 expression and short-term exposure to reprogramming media induces a state of transcriptional plasticity in human fibroblasts, capable of responding to changes in the extracellular environment. Here we provide characterization of iPSCs established through continued culture of OCT4-induced plastic human fibroblasts in pluripotent-supportive reprogramming media. Human iPSC(OCT4) are morphologically indistinguishable from conventionally derived iPSCs and express core proteins involved in maintenance of pluripotency. iPSC(OCT4) display bona fide functional pluripotency as measured by in vivo teratoma formation consisting of the three germ layers.

Reprogramming

Germ layer

10.1016/j.scr.2015.06.005

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Citations (1)