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Introduction

  • Gay M. Crooks
    Correspondence
    Offprint requests to: Gay M. Crooks, MBBS, 610 Charles E. Young Drive, East 3014 TLSB, Los Angeles, CA 90095
    Affiliations
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA

    Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA

    Broad Stem Cell Research Center, University of California, Los Angeles, CA

    Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA
    Search for articles by this author
  • Connie Eaves
    Affiliations
    British Columbia Cancer Research Centre, Vancouver, BC
    Search for articles by this author
Open ArchivePublished:February 12, 2019DOI:https://doi.org/10.1016/j.exphem.2019.02.001
      The biomedical field has been periodically revolutionized by major discoveries. A notable example was Evans and Kaufman's [
      • Evans M
      • Kaufman M
      Establishment in culture of pluripotent cells from mouse embryos.
      ] observation that cells from the inner cell mass of the mouse blastocyst could be propagated indefinitely in vitro with maintenance of their totipotentiality. The enormous potential of this technology to elucidate and manipulate processes regulating the development of the mouse was thus very rapidly realized. The subsequent creation of human embryonic stem cell (ESC) lines with analogous properties [
      • Thomson JA
      • Itskovitz-Eldor J
      • Shapiro SS
      • Waknitz MA
      • Swiergiel JJ
      • Marshall VS
      • Jones JM
      Embryonic stem cell lines derived from human blastocysts.
      ] expanded these avenues of experimental study to previously inaccessible stages of human development. In addition, they introduced the exciting prospect of generating new types of human cells and tissues for therapy. Biology was delivered a third seismic jolt when Takahashi et al. demonstrated that mature somatic cells from both mice [
      • Takahashi K
      • Yamanaka S
      Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.
      ] and humans [
      • Takahashi K
      • Tanabe K
      • Ohnuki M
      • Narita M
      • Ichisaka T
      • Tomoda K
      • Yamanaka S
      Induction of pluripotent stem cells from adult human fibroblasts by defined factors.
      ] could be reproducibly reprogrammed into a new type of “induced pluripotent stem cell” (iPSC) through the transient expression of only four factors. The rapid adoption of this methodology worldwide has now extended the reach of stem cell biology into patient-specific disease modeling and the production of HLA-identical tissues for clinical use.
      Interestingly, an understanding of many aspects of hematopoietic stem cell (HSC) biology was already well advanced before the first mouse ESC (mESC) and human ESC (hESC) lines were generated. Mouse HSC transplants had become routine experimental models and clinical applications of HSC-containing transplants became established, albeit imperfect, treatment modalities. Transfusions of red blood cells, platelets, and neutrophils were also standardized procedures and the potential of adoptive transfer of T cells for immunotherapy was being explored. Likewise, the unusual stepwise development of primitive hematopoietic cells in the embryo was recognized, as was the greater output potential of fetal and neonatal hematopoietic cells from both mice and humans. However, differences between mouse and human development and the limited access to late stages of human fetal development continue to retard progress in this field.
      Hematology was thus well primed to consider the use of ESCs and iPSCs for obtaining new insights and for developing new clinical applications for understanding and treating disease. However, since their discovery, ESC and iPSC technology has had an impact on the science of normal and malignant hematopoiesis that has been at the same time dramatic, illuminating, and frustrating. A decade later, the advances made are closing outstanding gaps and make a collation of these a timely exercise. This Special Issue was thus created to provide a compilation of current advances and challenges.
      The early accumulation of an extensive knowledge of HSC biology and its use in transplantation-based therapies initially led to the assumption that HSCs would likely be the first type of tissue-specific stem cells to be generated from ESCs and iPSCs and used clinically. However, the production from PSCs of long-term self-renewing HSCs with the properties of definitive HSCs has proven more difficult to realize than expected. Several groups have shown that the self-renewal capacity and durability of PSC-derived CD34+ hematopoietic cells can be enhanced by forced overexpression of certain transcription factors, but spontaneous production of cells with the properties of normal transplantable HSCs has to date eluded the field. Current evidence suggests that the differentiation of PSCs is often blocked at an embryonic stage of development, although recent findings have shown that mature functional lymphoid cells from the innate and adaptive immune system can be produced from PSCs.
      In this Special Issue, we begin with a review by Sluvkin and Uenishi [
      • Sluvkin II
      • Uenishi Gi
      Arterial identity of hemogenic endothelium: a key to unlock definitive hematopoietic commitment in human pluripotent stem cell cultures.
      ] on the process of the normal development of definitive HSCs. This review focuses on the arterial identity of hemogenic endothelium from which definitive HSCs arise, anticipating that an improved understanding of how these cells develop will be critical to the future generation of definitive human HSCs from PSCs. This is then followed by a contribution by Bernarrgegi, Pouyanfard, and Kaufman [
      • Bernarreggi D
      • Pouyanfard S
      • Kaufman DS
      Development of innate immune cells from human pluripotent stem cells.
      ] discussing the generation of natural killer (NK) cells and macrophages from PSCs and the clinical potential of PSC-derived NK cells armed with chimeric antigen receptors. Montel-Hagen and Crooks [
      • Montel-Hagen A
      • Crooks GM
      From pluripotent stem cells to T cells.
      ] then review the literature on the production of T cells from PSCs and discuss the recent development of “artificial thymic organoid” technology to allow positive selection and maturation of conventional T cells and genetic engineering approaches to arm these cells to kill tumor cells.
      Significant progress has also been made recently in using PSCs to model hematopoietic diseases. Three articles describe examples of models for benign hematopoietic disease. Elbadry, Espinoza and Nakao [
      • Elbadry MI
      • Espinoza JL
      • Nakao S
      Disease modeling of bone marrow failure syndromes using iPSC-derived hematopoietic stem progenitor cells.
      ] review the literature on the challenging field of bone marrow failure syndromes; Karagiannis, Yamanaka, and Saito [
      • Karagiannis P
      • Yamanaka S
      • Saito MK
      Application of induced pluripotent stem cells to primary immunodeficiency diseases.
      ] provide an overview of iPSCs and primary immune deficiency with a focus on specific disorders of innate immune cells such as neutrophils and monocyte–macrophages; and Dannenmann et al. [
      • Dannenmann B
      • Zahabi A
      • Mir P
      Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34+ cells preceding leukemic transformation.
      ] present original findings using iPSCs from patients with congenital neutropenia.
      The last trio of articles in this Special Issue summarize results from modeling hematopoietic malignancies using iPSCs. Turhan and colleagues [
      • Turhan A
      • Foudi A
      • Hwang JW
      • Desterke C
      • Griscelli F
      • Bennaceur-Griscelli A
      Modeling malignancies using induced pluripotent stem cells: from chronic myeloid leukemia to hereditary cancers.
      ] lay out the close biological relationship of cancer and cellular reprogramming, including the heterogeneity of cancers and the clonal development of certain cancers, findings that that have led to the cancer stem cell hypothesis. The article by Chao and Majeti [
      • Chao MP
      • Majeti R
      Induced pluripotent stem cell modeling of malignant hematopoiesis.
      ] then discusses the challenges presented by reprogramming the epigenome of malignant cells with retention of the original cancer phenotype. Finally, Papapetrou [
      • Papapetrou EP
      Modeling myeloid malignancies with patient-derived iPSCs.
      ] reviews experience in using patient-derived iPSC to model several human myeloid malignancies.
      As will be evident from these state-of-the art articles by leaders in the field, current understanding of the challenges and potential of this fascinating biological system to affect hematology in particular has now reached a new turning point. Due to space limitations, we are unable to specifically recognize the many others who have facilitated this progress. However, we expect that the ongoing international effort to understand how human PSCs can be coaxed into the many disparate lineages of hematopoiesis will continue at full force and will now be joined by an exciting new phase of disease modeling and clinical translation.

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        Arterial identity of hemogenic endothelium: a key to unlock definitive hematopoietic commitment in human pluripotent stem cell cultures.
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        • Pouyanfard S
        • Kaufman DS
        Development of innate immune cells from human pluripotent stem cells.
        Exp Hematol. 2019; 71: 13-23
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        • Crooks GM
        From pluripotent stem cells to T cells.
        Exp Hematol. 2019; 71: 24-31
        • Elbadry MI
        • Espinoza JL
        • Nakao S
        Disease modeling of bone marrow failure syndromes using iPSC-derived hematopoietic stem progenitor cells.
        Exp Hematol. 2019; 71: 32-42
        • Karagiannis P
        • Yamanaka S
        • Saito MK
        Application of induced pluripotent stem cells to primary immunodeficiency diseases.
        Exp Hematol. 2019; 71: 43-50
        • Dannenmann B
        • Zahabi A
        • Mir P
        Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34+ cells preceding leukemic transformation.
        Exp Hematol. 2019; 71: 51-60
        • Turhan A
        • Foudi A
        • Hwang JW
        • Desterke C
        • Griscelli F
        • Bennaceur-Griscelli A
        Modeling malignancies using induced pluripotent stem cells: from chronic myeloid leukemia to hereditary cancers.
        Exp Hematol. 2019; 71: 61-67
        • Chao MP
        • Majeti R
        Induced pluripotent stem cell modeling of malignant hematopoiesis.
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      Linked Article

      • Induced pluripotent stem cell modeling of malignant hematopoiesis
        Experimental HematologyVol. 71
        • Preview
          In 2012, the Nobel Prize in Physiology or Medicine was awarded to Sir John Gurdon and Shinya Yamanaka for the discovery that mature differentiated cells could be reprogrammed to a pluripotent state. By introducing four transcription factors (Sox2, Klf4, Oct3/4, and c-Myc), terminally differentiated cells can be epigenetically reprogrammed to an undifferentiated state [1]. Importantly, this epigenetic process does not alter the underlying genetic code of the parent cell. Therefore, these induced pluripotent stem cells (iPSCs) have significant applications in disease biology, including the ability to create novel disease models of human genetic disease for biologic discovery.
        • Full-Text
        • PDF
        Open Archive
      • Modeling myeloid malignancies with patient-derived iPSCs
        Experimental HematologyVol. 71
        • Preview
          The derivation of human induced pluripotent stem cells (iPSCs) in 2007 ushered in a new era in the modeling of human diseases, including those affecting the hematopoietic system [1–3]. Significant advances over the past decade have enabled investigators to increasingly incorporate iPSC models in their research. iPSCs can empower diverse research studies, ranging from investigations into basic disease mechanisms to more translational applications such as therapeutic target discovery, drug testing, compound screening, toxicity testing, and generation of cells for transplantation [2,4].
        • Full-Text
        • PDF
        Open Archive
      • Application of induced pluripotent stem cells to primary immunodeficiency diseases
        Experimental HematologyVol. 71
        • Preview
          Primary immunodeficiency diseases (PIDs) describe a group of clinically and genetically heterogeneous disorders that afflict lymphoid and myeloid lineages. PIDs have been recognized for a century, but the first molecular cause was not reported until 1972, when scientists realized that a child with severe combined immune deficiency (SCID) completely lacked adenosine deaminase, eventually leading to enzyme replacement therapy [1,2]. There are now a number of therapeutic options for PIDs, including cytokine-based strategies, gene therapies, and hematopoietic stem cell (HSC) transplantation [3–5].
        • Full-Text
        • PDF
        Open Archive
      • Development of innate immune cells from human pluripotent stem cells
        Experimental HematologyVol. 71
        • Preview
          Mouse and human pluripotent stem cells have been widely used to study the development of the hematopoietic and immune systems. Although not all cells can be derived with the same efficiency, immune cells such as natural killer (NK) cells and macrophages can be easily produced from PSCs to enable development of new cell-based therapies. NK cells and macrophages are part of the innate immune system, the first line of defense against malignancies and infectious disease. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived NK cells can be produced at a clinical scale suitable for translation into clinical trials.
        • Full-Text
        • PDF
        Open Archive
      • From pluripotent stem cells to T cells
        Experimental HematologyVol. 71
        • Preview
          The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T-cell immunotherapy. After directing PSCs through mesoderm and early hematopoietic developmental stages, commitment to the T-cell lineage has been achieved by several groups using coculture with stromal cells that express a notch ligand, recapitulating the critical signals that initiate the first stages of normal T-cell differentiation in the thymus.
        • Full-Text
        • PDF
        Open Archive
      • Arterial identity of hemogenic endothelium: a key to unlock definitive hematopoietic commitment in human pluripotent stem cell cultures
        Experimental HematologyVol. 71
        • Preview
          Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the de novo production of blood cells for transfusion, immunotherapies, and transplantation. However, even with advanced hematopoietic differentiation methods, the primitive and myeloid-restricted waves of hematopoiesis dominate in hPSC differentiation cultures, whereas cell surface markers to distinguish these waves of hematopoiesis from lympho-myeloid hematopoiesis remain unknown. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries, but not veins.
        • Full-Text
        • PDF
        Open Archive
      • Modeling malignancies using induced pluripotent stem cells: from chronic myeloid leukemia to hereditary cancers
        Experimental HematologyVol. 71
        • Preview
          The seminal discovery of cell reprogramming in 2006 by Shinya Yamanaka opened up novel and unprecedented perspectives, not only in the field of biology in general, but also in all fields of medicine, with almost endless possibilities in terms of therapeutic applications [1]. Although the use of induced pluripotent stem cells (iPSCs) appeared initially as a technique that would be widely applicable alternatives to embryonic stem cells (ESCs), several hurdles remain to be solved for the use of iPSCs and their derivatives in regenerative medicine.
        • Full-Text
        • PDF
        Open Archive
      • Disease modeling of bone marrow failure syndromes using iPSC-derived hematopoietic stem progenitor cells
        Experimental HematologyVol. 71
        • Preview
          Aplastic anemia (AA) is a life-threatening bone marrow failure (BMF) disorder, resulting in bone marrow hypoplasia, infection and hemorrhage, and severe peripheral pancytopenia. Although the most cases of AA are acquired and associated with the autoimmune destruction of hematopoietic stem progenitor cells (HSPCs) in the BM, in some cases, the BMF is caused by genetic or inherited anomalies that impair hematopoiesis [1]. The destruction or dysfunction of HSPCs in the BM of patients with BMF syndromes (BMFSs) limits the study of these disorders because the use of conventional in vitro HSPC culture or in vivo animal models for creating patient-specific disease modeling is technically impossible due to the unavailability of patient-derived HSPCs.
        • Full-Text
        • PDF
        Open Archive
      • Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34+ cells preceding leukemic transformation
        Experimental HematologyVol. 71
        • Preview
          Severe congenital neutropenia (CN) is a monolineage preleukemia bone marrow failure syndrome characterized by early onset of neutropenia and severe infections due to promyelocytic maturational arrest in the bone marrow [1,2]. CN is a heterogeneous disease caused by mutations in a number of genes, including ELANE [3] (the most common [1]), HAX1 [4], CSF3R [5,6], JAGN1 [7], G6PC3 [8], TCIRG1 [9], and others. In most cases, ELANE mutations are missense mutations that are distributed throughout all five exons of the ELANE gene, although a majority of mutations are found in exons 4 and 5 [10].
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        Open Archive