Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

Gori, Jennifer L.; Butler, Jason M.; Chan, Yan Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans Peter

doi:10.1172/jci79328

Cited by 96 publications

(95 citation statements)

References 61 publications

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“…As such, these data show that the acquisition of multilineage hematopoietic progenitors is possible using an in vitro vascular induction methodology. Our data are highly relevant and complement other studies utilizing VeraVec coculture to promote in vitro conditions for the specification of alternate cell types to transplantable and engraftable HSPCs and are additive to the cellular engineering field [36,54].…”

Section: Discussionsupporting

confidence: 72%

CRISPR/Cas9 Targeted Gene Editing and Cellular Engineering in Fanconi Anemia

Osborn

Lonetree

Webber

et al. 2016

Stem Cells and Development

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Section: Discussionsupporting

confidence: 72%

CRISPR/Cas9 Targeted Gene Editing and Cellular Engineering in Fanconi Anemia

Osborn

Lonetree

Webber

et al. 2016

Stem Cells and Development

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“…However, at present, the clinical usage of iPSCs for the treatment of hematopoietic disorders remains a challenge due to difficulties with the efficient in vitro production of engraftable HSPCs from human iPSCs, 28 despite recent advancements. 29 Direct gene correction of engraftable somatic HSPCs could Also shown is a portion of the CYBB-E1-13 donor plasmid construct, containing homology arms (LHA and RHA) to regions flanking the insertion site, surrounding the CYBB exon 1-13 cDNA (either codon-optimized or normal) followed by poly(A) signal (pA) and a loxP-flanked CMV promoter-driven puromycin resistance drug selection cassette (puro). Gray arrowheads denote locations of PCR primers used for screening for random insertions of the donor in which portions of the plasmid backbone outside of the homology arms are retained.…”

Section: Discussionmentioning

confidence: 99%

Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction

et al. 2017

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X-linked chronic granulomatous disease (X-CGD) is an immune deficiency resulting from defective production of microbicidal reactive oxygen species (ROS) by phagocytes. Causative mutations occur throughout the CYBB gene, resulting in absent or defective gp91 phox protein expression. To correct CYBB exon 5 mutations while retaining normal gene regulation, we utilized TALEN or Cas9 for exon 5 replacement in induced pluripotent stem cells (iPSCs) from patients, which restored gp91 phox expression and ROS production in iPSCderived granulocytes. Alternate approaches for correcting the majority of X-CGD mutations were assessed, involving TALEN-or Cas9-mediated insertion of CYBB minigenes at exon 1 or 2 of the CYBB locus. Targeted insertion of an exon 1-13 minigene into CYBB exon 1 resulted in no detectable gp91 phox expression or ROS activity in iPSC-derived granulocytes. In contrast, targeted insertion of an exon 2-13 minigene into exon 2 restored both gp91 phox and ROS activity. This demonstrates the efficacy of two correction strategies: seamless repair of specific CYBB mutations by exon replacement or targeted insertion of an exon 2-13 minigene to CYBB exon 2 while retaining exon/intron 1. Furthermore, it highlights a key issue for targeted insertion strategies for expression from an endogenous promoter: retention of intronic elements can be necessary for expression.

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“…78,79 An extensive transcriptome profiling of megakaryocytes derived from each of these developmental stages has identified differentially expressed sets of genes that can be grouped into primitive and definitive gene profiles. 27 Comparing embryonic, fetal liver, cord blood, and adult-derived megakaryocytes, this study highlights phenotypic and genotypic differences at these developmental stages and shows that ESC-derived megakaryocytes represent the primitive lineage.…”

Section: Stem Cell Choicementioning

confidence: 99%

Understanding platelet generation from megakaryocytes: implications for in vitro–derived platelets

Sim

Poncz

Gadue

et al. 2016

Blood

101

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Platelets are anucleate cytoplasmic discs derived from megakaryocytes that circulate in the blood and have major roles in hemostasis, thrombosis, inflammation, and vascular biology. Platelet transfusions are required to prevent the potentially life-threatening complications of severe thrombocytopenia seen in a variety of medical settings including cancer therapy, trauma, and sepsis. Platelets used in the clinic are currently donor-derived which is associated with concerns over sufficient availability, quality, and complications due to immunologic and/or infectious issues. To overcome our dependence on donor-derived platelets for transfusion, efforts have been made to generate in vitro–based platelets. Work in this area has advanced our understanding of the complex processes that megakaryocytes must undergo to generate platelets both in vivo and in vitro. This knowledge has also defined the challenges that must be overcome to bring in vitro–based platelet manufacturing to a clinical reality. This review will focus on our understanding of committed megakaryocytes and platelet release in vivo and in vitro, and how this knowledge can guide the development of in vitro–derived platelets for clinical application.

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Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

Cited by 96 publications

References 61 publications

CRISPR/Cas9 Targeted Gene Editing and Cellular Engineering in Fanconi Anemia

CRISPR/Cas9 Targeted Gene Editing and Cellular Engineering in Fanconi Anemia

Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction

Understanding platelet generation from megakaryocytes: implications for in vitro–derived platelets

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