Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell–derived hematopoietic progenitor cells

Chan, Kun‐Ming; Bonde, Sabrina; Klump, Hannes; Zavazava, Nicholas

doi:10.1182/blood-2007-10-117366

Cited by 53 publications

(97 citation statements)

References 31 publications

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“…(Ϫ/Ϫ) ␥C (Ϫ/Ϫ) mice in vivo from differentiating mouse ESCs, in vitro [23,24]. For ESC-derived HSPC development to occur, certain threshold levels of HOXB4 expression need to be exceeded (S. Pilat, S. Carotta, B. Schiedlmeier et al, manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

“…So far, robust production of definitive HSCs from mouse ESCs capable of long-term multilineage reconstitution of adult recipient animals has been achieved only by enforced ectopic expression of either human HOXB4 alone or human HOXB4 in combination with Cdx4 [21][22][23][24]. In this experimental system, ESC-derived HSCs exhibit a unique mixed expression of cell surface markers characteristic of both embryonic and adult, mature HSCs.…”

Section: Embryonic Stem Cells/induced Pluripotent Stem (Ips) Cellsmentioning

confidence: 99%

“…It is noteworthy that a bias toward myelopoiesis (GFP ϩ CD11b ϩ ) and away from lymphopoiesis (GFP ϩ CD3 ϩ ) was observed in vivo (Fig. 4B), which is a well-known effect of HOXB4 activity [21][22][23][24]. Lymphoid cells, which develop from the HOXB4-expressing HSPCs after transplantation in vivo, commonly display a selective silencing of ectopic retroviral HOXB4 expression (as described in Discussion).…”

Section: Hypoxic Conditions In Vitro Support Esc-hc Engraftment In Immentioning

confidence: 99%

“…(Ϫ/Ϫ) mice [21][22][23][24], which do not possess any lymphoid cells per se. Because lymphoid cells are generated in the immunodeficient mice, HOXB4 must be able to promote the development of multipotent lymphomyeloid hematopoietic progenitors in vitro and at least allow development of common lymphoid progenitors in vivo.…”

Section: ␥Cmentioning

confidence: 99%

“…(Ϫ/Ϫ) ␥C (Ϫ/Ϫ) immunodeficient mice [24] (S. Pilat, personal communication). As a first step, we analyzed the specification of hematopoietic cells from day 6 to day 10 of EB formation (EBd6 -EBd10) under different conditions.…”

Section: Rag2mentioning

confidence: 99%

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Serum- and Stromal Cell-Free Hypoxic Generation of Embryonic Stem Cell-Derived Hematopoietic Cells In Vitro, Capable of Multilineage Repopulation of Immunocompetent Mice

Lesinski

Heinz

Pilat-Carotta

et al. 2012

Stem Cells Translational Medicine

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Induced pluripotent stem cells (iPSCs) may become a promising source for the generation of patientspecific hematopoietic stem cells (HSCs) in vitro. A crucial prerequisite will be the availability of reliable protocols for the directed and efficient differentiation toward HSCs. So far, the most robust strategy for generating HSCs from pluripotent cells in vitro has been established in the mouse model involving ectopic expression of the human transcription factor HOXB4. However, most differentiation protocols include coculture on a xenogenic stroma cell line and the use of animal serum. Involvement of any of both would pose a major barrier to the translation of those protocols to human autologous iPSCs intended for clinical use. Therefore, we asked whether long-term repopulating HSCs can, in principle, be generated from embryonic stem cells without stroma cells or serum. Here, we showed that long-term multilineage engraftment could be accomplished in immunocompetent mice when HSCs were generated in serum-free medium without stroma cell support and when hypoxic conditions were used. Under those conditions, HOXB4؉ embryonic stem cell-derived hematopoietic stem and progenitor cells were immunophenotypically similar to definitive bone marrow resident E-SLAM ؉ (CD150 ؉ CD48 − CD45 ؉ CD201 ؉ ) HSCs. Thus, our findings may ease the development of definitive, adult-type HSCs from pluripotent stem cells, entirely in vitro. STEM CELLS TRANSLATIONAL MEDICINE 2012;1:581-591

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Section: Discussionmentioning

confidence: 99%

Section: Embryonic Stem Cells/induced Pluripotent Stem (Ips) Cellsmentioning

confidence: 99%

Section: Hypoxic Conditions In Vitro Support Esc-hc Engraftment In Immentioning

confidence: 99%

Section: ␥Cmentioning

confidence: 99%

Section: Rag2mentioning

confidence: 99%

See 3 more Smart Citations

Serum- and Stromal Cell-Free Hypoxic Generation of Embryonic Stem Cell-Derived Hematopoietic Cells In Vitro, Capable of Multilineage Repopulation of Immunocompetent Mice

Lesinski

Heinz

Pilat-Carotta

et al. 2012

Stem Cells Translational Medicine

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Mechanism of Action of HOXB4 on the Hematopoietic Differentiation of Embryonic Stem Cells

Forrester

Jackson

2012

STEM CELLS

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Pluripotent stem cells can be differentiated into hematopoietic lineages in vitro and hold promise for the future treatment of hematological disease. Differentiation strategies involving defined factors in serum‐free conditions have been successful in producing hematopoietic progenitors and some mature cell types from mouse and human embryonic stem cells and induced pluripotent cells. However, these precisely defined protocols are relatively inefficient and have not been used successfully to produce hematopoietic stem cells capable of multilineage long‐term reconstitution of the hematopoietic system. More complex differentiation induction strategies including coculture with stromal cells derived from sites of hematopoietic activity in vivo and enforced expression of reprogramming transcription factors, such as HOXB4, have been required to increase the efficiency of the differentiation procedure and to produce these most potent hematopoietic stem cells. We review the studies that have used HOXB4 to improve hematopoietic differentiation from pluripotent cells focusing on studies that have provided some insight into its mechanism of action. A better understanding of the molecular pathways involved in the action of HOXB4 might lead to more defined culture systems and safer protocols for clinical translation. STEM CELLS 2012;30:379–385

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Generation of iPSCs from Genetically Corrected Brca2 Hypomorphic Cells: Implications in Cell Reprogramming and Stem Cell Therapy

et al. 2014

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Fanconi anemia (FA) is a complex genetic disease associated with a defective DNA repair pathway known as the FA pathway. In contrast to many other FA proteins, BRCA 2 participates downstream in this pathway and has a critical role in homology-directed recombination (HDR). In our current studies, we have observed an extremely low reprogramming efficiency in cells with a hypomorphic mutation in Brca2 (Brca2), that was associated with increased apoptosis and defective generation of nuclear RAD51 foci during the reprogramming process. Gene complementation facilitated the generation of Brca2 D27/D27 induced pluripotent stem cells (iPSCs) with a disease-free FA phenotype. Karyotype analyses and comparative genome hybridization arrays of complemented Brca2 D27/D27 iPSCs showed, however, the presence of different genetic alterations in these cells, most of which were not evident in their parental Brca2 D27/D27 mouse embryonic fibroblasts. Gene-corrected Brca2 D27/D27 iPSCs could be differentiated in vitro toward the hematopoietic lineage, although with a more limited efficacy than WT iPSCs or mouse embryonic stem cells, and did not engraft in irradiated Brca2 D27/D27 recipients. Our results are consistent with previous studies proposing that HDR is critical for cell reprogramming and demonstrate that reprogramming defects characteristic of Brca2 mutant cells can be efficiently overcome by gene complementation. Finally, based on analysis of the phenotype, genetic stability, and hematopoietic differentiation potential of gene-corrected Brca2 D27/D27 iPSCs, achievements and limitations in the application of current reprogramming approaches in hematopoietic stem cell therapy are also discussed. STEM CELLS 2014;32:436-446

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Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell–derived hematopoietic progenitor cells

Cited by 53 publications

References 31 publications

Serum- and Stromal Cell-Free Hypoxic Generation of Embryonic Stem Cell-Derived Hematopoietic Cells In Vitro, Capable of Multilineage Repopulation of Immunocompetent Mice

Serum- and Stromal Cell-Free Hypoxic Generation of Embryonic Stem Cell-Derived Hematopoietic Cells In Vitro, Capable of Multilineage Repopulation of Immunocompetent Mice

Mechanism of Action of HOXB4 on the Hematopoietic Differentiation of Embryonic Stem Cells

Generation of iPSCs from Genetically Corrected Brca2 Hypomorphic Cells: Implications in Cell Reprogramming and Stem Cell Therapy

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