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mickie bhatia

Allison L Boyd, Mickie Bhatia
Increasing attention has been focused on the interactions between leukemia cells and their bone marrow (BM) microenvironment. We have recently shown that leukemic stem cells (LSCs) share common BM "niches" with their healthy counterparts. As a result of these shared niche requirements, human LSCs can be mobilized using existing pharmacological agents that facilitate competitive healthy reconstitution, leading to eradication of leukemia during BM transplantation.
July 2015: Molecular & Cellular Oncology
Borhane Guezguez, Mohammed Almakadi, Yannick D Benoit, Zoya Shapovalova, Susann Rahmig, Aline Fiebig-Comyn, Fanny L Casado, Borko Tanasijevic, Silvia Bresolin, Riccardo Masetti, Bradley W Doble, Mickie Bhatia
Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3β dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3β deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3β and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively...
January 11, 2016: Cancer Cell
Chitra Venugopal, Robin Hallett, Parvez Vora, Branavan Manoranjan, Sujeivan Mahendram, Maleeha A Qazi, Nicole McFarlane, Minomi Subapanditha, Sara M Nolte, Mohini Singh, David Bakhshinyan, Neha Garg, Thusyanth Vijayakumar, Boleslaw Lach, John P Provias, Kesava Reddy, Naresh K Murty, Bradley W Doble, Mickie Bhatia, John A Hassell, Sheila K Singh
PURPOSE: Clonal evolution of cancer may be regulated by determinants of stemness, specifically self-renewal, and current therapies have not considered how genetic perturbations or properties of stemness affect such functional processes. Glioblastoma-initiating cells (GICs), identified by expression of the cell surface marker CD133, are shown to be chemoradioresistant. In the current study, we sought to elucidate the functional role of CD133 in self-renewal and identify compounds that can specifically target this CD133(+) treatment-refractory population...
December 1, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kyle R Salci, Jung Bok Lee, Ryan R Mitchell, Luca Orlando, Aline Fiebig-Comyn, Zoya Shapovalova, Mickie Bhatia
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...
July 2015: Stem Cell Research
Kyle R Salci, Jung Bok Lee, Ryan R Mitchell, Luca Orlando, Aline Fiebig-Comyn, Zoya Shapovalova, Mickie Bhatia
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...
July 2015: Stem Cell Research
Jong-Hee Lee, Ryan R Mitchell, Jamie D McNicol, Zoya Shapovalova, Sarah Laronde, Borko Tanasijevic, Chloe Milsom, Fanny Casado, Aline Fiebig-Comyn, Tony J Collins, Karun K Singh, Mickie Bhatia
The clinical applicability of direct cell fate conversion depends on obtaining tissue from patients that is easy to harvest, store, and manipulate for reprogramming. Here, we generate induced neural progenitor cells (iNPCs) from neonatal and adult peripheral blood using single-factor OCT4 reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, OCT4 reprogramming of blood was facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood-derived (BD) iNPCs differentiate in vivo and respond to guided differentiation in vitro, producing glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes, including dopaminergic (CNS related) and nociceptive neurons (peripheral nervous system [PNS])...
June 9, 2015: Cell Reports
Kyle R Salci, Jong-Hee Lee, Sarah Laronde, Steve Dingwall, Rahul Kushwah, Aline Fiebig-Comyn, Brian Leber, Ronan Foley, Arianna Dal Cin, Mickie Bhatia
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...
June 2015: Stem Cells
Jong-Hee Lee, Jung Bok Lee, Zoya Shapovalova, Aline Fiebig-Comyn, Ryan R Mitchell, Sarah Laronde, Eva Szabo, Yannick D Benoit, Mickie Bhatia
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...
2014: Nature Communications
Brendan A S McIntyre, Rahul Kushwah, Rami Mechael, Zoya Shapovalova, Cantas Alev, Mickie Bhatia
The acquisition of innate immune response is requisite to having bona fide differentiation of airway epithelium. Procedures developed to differentiate lung airway from human pluripotent stem cells (hPSCs) have demonstrated anecdotal evidence for innate immune response, but an in-depth exploration of response levels is lacking. Herein, using an established method of airway epithelial generation from hPSCs, we show that hPSC-derived epithelial cells are able to up-regulate expression of TNFα, IL8 and IL1β in response to challenge with bacterial endotoxin LPS, but lack response from genes associated with innate immune response in other cell types...
July 2015: Innate Immunity
Rahul Kushwah, Borhane Guezguez, Jung Bok Lee, Claudia I Hopkins, Mickie Bhatia
The Notch signaling pathway is evolutionarily conserved across species and plays an important role in regulating cell differentiation, proliferation, and survival. It has been implicated in several different hematopoietic processes including early hematopoietic development as well as adult hematological malignancies in humans. This review focuses on recent developments in understanding the role of Notch signaling in the human hematopoietic system with an emphasis on hematopoietic initiation from human pluripotent stem cells and regulation within the bone marrow...
November 2014: EMBO Reports
Allison L Boyd, Clinton J V Campbell, Claudia I Hopkins, Aline Fiebig-Comyn, Jennifer Russell, Jelena Ulemek, Ronan Foley, Brian Leber, Anargyros Xenocostas, Tony J Collins, Mickie Bhatia
Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous...
September 22, 2014: Journal of Experimental Medicine
Yannick D Benoit, Borhane Guezguez, Allison L Boyd, Mickie Bhatia
Aberrant regulation of the canonical Wnt signaling pathway (Wnt-β-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-β-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved...
November 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Allison L Boyd, Mickie Bhatia
PURPOSE OF REVIEW: Historically, studies of the hematopoietic stem cell (HSC) microenvironment in bone marrow have focused on the identification of individual supportive cell lineages likely to be responsible for maintaining HSCs in a self-renewing and regenerative state. More recently, awareness has developed regarding the broad and dynamic heterogeneity of nonhematopoietic cells that reside within the bone marrow space. We review recent insights that provide an emerging and complex context for understanding the spatially dependent regulation of HSC functional properties in the bone marrow and the collective inputs of multiple cell types...
July 2014: Current Opinion in Hematology
Borhane Guezguez, Mickie Bhatia
No abstract text is available yet for this article.
2014: Cell Cycle
Ryan Mitchell, Eva Szabo, Zoya Shapovalova, Lili Aslostovar, Kennedy Makondo, Mickie Bhatia
Here we characterize the molecular and biological requirements for OCT4 plasticity induction in human skin derived fibroblasts (hFibs) that allows direct conversion of cell fate without iPSC formation. Our results indicate that adult hFibs not only require OCT4 but also short-term exposure to reprogramming media (RM) to successfully undergo direct conversion to early hematopoietic and neural progenitor fates. RM was found to be essential in this process and allowed for unique changes in global gene expression specific to the combined effects of OCT4 and treatment with reprogramming media to establish a plastic state...
August 2014: Stem Cells
Ryan R Mitchell, Eva Szabo, Yannick D Benoit, Daniel T Case, Rami Mechael, Javier Alamilla, Jong Hee Lee, Aline Fiebig-Comyn, Deda C Gillespie, Mickie Bhatia
Several transcription factors and methods have been used to convert fibroblasts directly to neural fate and have provided insights into molecular mechanisms as to how each of these required factors orchestrate neural fate conversion. Here, we provide evidence and detailed characterization of the direct conversion process of primary adult human fibroblasts (hFib) to neural progenitor cells (NPC) using OCT4 alone. Factors previously associated with neural cell fate conversion were induced during hFib-NPC(OCT-4) generation, where OCT-4 alone was sufficient to induce neural fate conversion without the use of promiscuous small-molecule manipulation...
August 15, 2014: Stem Cells and Development
Brendan A S McIntyre, Cantas Alev, Rami Mechael, Kyle R Salci, Jung Bok Lee, Aline Fiebig-Comyn, Borhane Guezguez, Yuping Wu, Guojun Sheng, Mickie Bhatia
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...
January 2014: Stem Cells Translational Medicine
Borhane Guezguez, Clinton J V Campbell, Allison L Boyd, Francis Karanu, Fanny L Casado, Christine Di Cresce, Tony J Collins, Zoya Shapovalova, Anargyros Xenocostas, Mickie Bhatia
Numerous studies have shown that the bone marrow (BM) niche plays a key role in mouse hematopoietic stem cell (HSC) function and involves contributions from a broad array of cell types. However, the composition and role of the human BM HSC niche have not been investigated. Here, using human bone biopsy specimens, we provide evidence of HSC propensity to localize to endosteal regions of the trabecular bone area (TBA). Through functional xenograft transplantation, we found that human HSCs localizing to the TBA have superior regenerative and self-renewal capacity and are molecularly distinct from those localizing to the long bone area (LBA)...
August 1, 2013: Cell Stem Cell
Angelique Schnerch, Shravanti Rampalii, Mickie Bhatia
Comparing normal human embryonic stem cells (hESCs) to those that have acquired cellular properties of neoplasm provides a unique opportunity to study the distinguishing molecular features of human cellular transformation. As global alterations in the epigenetic landscape are a common feature of cancer, we sought to investigate the loci-specific and global differences between normal and transformed hESCs using ChIP-PCR and ChIP-microarray (also known as ChIP-chip). Here, specific emphasis was placed on optimizing ChIP for low cell numbers (termed micro-ChIP; μChIP) towards applications where the target population is rare, such as the case for somatic human tumors containing a low frequency of cancer stem cell populations and for single-colony analysis of embryonic and induced pluripotent stem cells emerging from initial derivation...
2013: Methods in Molecular Biology
Allison L Boyd, Kyle R Salci, Zoya Shapovalova, Brendan A S McIntyre, Mickie Bhatia
Recent work has shown that leukemic stem cell self-renewal in chronic myeloid leukemia is dependent on cell-intrinsic hedgehog (Hh) signaling, and early clinical trials suggest that targeting this pathway is also therapeutic in patients with acute myeloid leukemia (AML). In this study, we aimed to better understand Hh signaling in normal hematopoiesis and AML by molecularly and functionally analyzing more than 200 primary human AML patient samples compared with nonleukemic controls. Gene expression analysis indicated that Hh pathway transcripts were similarly regulated in AML and nonleukemic controls, regardless of whether samples were purified based on primitive phenotypes...
October 2013: Experimental Hematology
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