Induced pluripotent stem cells in hematology: current and future applications

Focosi, Daniele; Amabile, Giovanni; Ruscio, Annalisa Di; Quaranta, Paola; Tenen, Daniel G.; Pistello, Mauro

doi:10.1038/bcj.2014.30

Cited by 22 publications

(16 citation statements)

References 84 publications

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“…Besides the generation of distinct hematopoietic lineages, the generation of HSCs from hiPSCs is a central purpose of biomedical research and transfusion medicine in particular [24,25]. Although significant efforts were done, true HSCs with long-term engraftment potential cannot be expanded indefinitely in vitro until now [26,27].…”

Section: Discussionmentioning

confidence: 99%

Emergence of CD43-Expressing Hematopoietic Progenitors from Human Induced Pluripotent Stem Cells

Kessel¹,

Bluemke²,

Schöler³

et al. 2017

Transfus Med Hemother

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Background: The ex vivo generation of human hematopoietic stem cells (HSCs) with long-term repopulating capacity and multi-lineage differentiation potential represents the holy grail of hematopoiesis research. In principle, human induced pluripotent stem cells (hiPSCs) provide the tool for both studying molecular mechanisms of hematopoietic development and the ex vivo production of ‘true' HSCs for transplantation purposes and lineage-specific cells, e.g. red blood cells, for transfusion purposes. CD43-expressing cells have been reported as the first hematopoietic cells during development, but whether or not these possess multilineage differentiation and long-term engraftment potential is incompletely understood. Methods: We performed ex vivo generation of hematopoietic cells from hiPSCs using an embryoid body(EB)-based, xeno-product-free differentiation protocol. We investigated the multilineage differentiation potential of different FACS-sorted CD43-expressing cell subsets by colony-forming assays in semisolid media. Further, erythroid differentiation was investigated in more detail using established protocols. Results: By using CD43, we were able to measure hematopoietic induction efficiency during hiPSC-derived EB differentiation. Further, we determined CD43+ cells as the cell population of origin for in vitro erythropoiesis. Furthermore, colony formation demonstrates that the multipotent hematopoietic stem and progenitor cell fraction is particulary enriched in the CD43^hi CD45+ population.

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Section: Discussionmentioning

confidence: 99%

Emergence of CD43-Expressing Hematopoietic Progenitors from Human Induced Pluripotent Stem Cells

Kessel¹,

Bluemke²,

Schöler³

et al. 2017

Transfus Med Hemother

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“…Hence, human iPSCs (hiPSCs) represent an ideal source to produce patient‐specific biological material. For example, in genetic hematologic disorders, we and others have developed potent protocols for in vitro hematopoietic differentiation of stem cells after they have been genetically corrected . However, several aspects hinder the progression of iPSCs into clinic.…”

Section: Introductionmentioning

confidence: 99%

Preventing Pluripotent Cell Teratoma in Regenerative Medicine Applied to Hematology Disorders

Bedel

Beliveau

Lamrissi-Garcia

et al. 2016

Stem Cells Translational Medicine

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Iatrogenic tumorigenesis is a major limitation for the use of human induced pluripotent stem cells (hiPSCs) in hematology. The teratoma risk comes from the persistence of hiPSCs in differentiated cell populations. Our goal was to evaluate the best system to purge residual hiPSCs before graft without compromising hematopoietic repopulation capability. Teratoma risk after systemic injection of hiPSCs expressing the reporter gene luciferase was assessed for the first time. Teratoma formation in immune‐deficient mice was tracked by in vivo bioimaging. We observed that systemic injection of hiPSCs produced multisite teratoma as soon as 5 weeks after injection. To eliminate hiPSCs before grafting, we tested the embryonic‐specific expression of suicide genes under the control of the pmiR‐302/367 promoter. This promoter was highly active in hiPSCs but not in differentiated cells. The gene/prodrug inducible Caspase‐9 (iCaspase‐9)/AP20187 was more efficient and rapid than thymidine kinase/ganciclovir, fully specific, and without bystander effect. We observed that iCaspase‐9‐expressing hiPSCs died in a dose‐dependent manner with AP20187, without reaching full eradication in vitro. Unexpectedly, nonspecific toxicity of AP20187 on iCaspase‐9‐negative hiPSCs and on CD34+ cells was evidenced in vitro. This toxic effect strongly impaired CD34+‐derived human hematopoiesis in adoptive transfers. Survivin inhibition is an alternative to the suicide gene approach because hiPSCs fully rely on survivin for survival. Survivin inhibitor YM155 was more efficient than AP20187/iCaspase‐9 for killing hiPSCs, without toxicity on CD34+ cells, in vitro and in adoptive transfers. hiPSC purge by survivin inhibitor fully eradicated teratoma formation in immune‐deficient mice. This will be useful to improve the safety management for hiPSC‐based medicine. Stem Cells Translational Medicine 2017;6:382–393

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“…Following development of induced pluripotent stem cell (iPSC) technologies in 2006 (Takahashi and Yamanaka 2006), therapeutic potential of gene targeting in iPSCs was demonstrated, including for hematological diseases (Kim 2014a; Focosi et al 2014; Singh et al 2015). In one example, Hanna et al derived somatic cells from a humanized sickle cell anemia mouse model, reprogrammed the cells into iPSCs, corrected the sickle mutation in iPSCs by HR and differentiated iPSCs into hematopoietic progenitors to be transplanted back into the mouse (Hanna et al 2007).…”

Section: Gene Targeting As a Strategy For Sickle Cell Therapeuticsmentioning

confidence: 99%

“…We will discuss three important issues: efficiency, off-target effects and safe delivery methods. As mentioned in previous sections, issues with stem cell transplantation that are not directly related to the use of programmable nucleases are beyond the scope of this paper and can be found in other reviews (Lengerke and Daley 2010; Arora and Daley 2012; Slukvin 2013; Kim 2014a; Focosi et al 2014; Singh et al 2015; Ackermann et al 2015). …”

Section: Major Obstacles In Translation Of Gene Editing Tools For mentioning

confidence: 99%

Use of genome-editing tools to treat sickle cell disease

2016

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Recent advances in genome editing techniques have made it possible to modify any desired DNA sequence by employing programmable nucleases. These next generation genome-modifying tools are the ideal candidates for therapeutic applications, especially for the treatment of genetic disorders like sickle cell disease (SCD). SCD is an inheritable monogenic disorder which is caused by a point mutation in the β-globin gene. Substantial success has been achieved in the development of supportive therapeutic strategies for SCD but unfortunately there is still a lack of long-term universal cure. The only existing curative treatment is based on allogeneic stem cell transplantation from healthy donors; however, this treatment is applicable to a limited number of patients only. Hence, a universally applicable therapy is highly desirable. In this review we will discuss the three programmable nucleases that are commonly used for genome editing purposes: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9). We will continue by exemplifying uses of these methods to correct the sickle cell mutation. Additionally, we will present induction of fetal globin expression as an alternative approach to cure sickle cell disease. We will conclude by comparing the three methods and explaining the concerns about their use in therapy.

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Induced pluripotent stem cells in hematology: current and future applications

Cited by 22 publications

References 84 publications

Emergence of CD43-Expressing Hematopoietic Progenitors from Human Induced Pluripotent Stem Cells

Emergence of CD43-Expressing Hematopoietic Progenitors from Human Induced Pluripotent Stem Cells

Preventing Pluripotent Cell Teratoma in Regenerative Medicine Applied to Hematology Disorders

Use of genome-editing tools to treat sickle cell disease

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