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Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for...
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Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (15 December 2021) | Viewed by 27513

Special Issue Editor

Dr. Andre Larochelle

E-Mail Website
Guest Editor
National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Bethesda, MD, USA
Interests: hematopoietic stem cell; gene therapy; gene editing; iPSC; hematopoiesis; inherited blood disorder; eltrombopag

Special Issue Information

Dear Colleagues,

With Yamanaka’s landmark reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) in 2006, the appealing concept of generating iPSCs from an individual patient, correcting the genetic defect and differentiating the disease-free iPSCs into a theoretically infinite supply of transplantable autologous Hematopoietic Stem/Progenitor Cells (HSPCs) arose. However, despite recent promising reports, efficient derivation of functional HSPCs with a robust capability for definitive in vivo engraftment and multilineage potential remains challenging. Therefore, clinically feasible strategies to advance the current state of de novo HSPC generation are needed.  

This Special Issue solicits original research manuscripts and review articles on topics related to the generation of HSPCs from pluripotent stem cells (PSCs)—including, but not limited to, developmental hematopoiesis, strategies for HSPC derivation (e.g., directed differentiation, conversion), characterization of PSC-derived hematopoietic cells (e.g., transcriptome, epigenome), hematopoietic disease modelling, genetic correction/editing and differentiation of disease-specific PSCs, etc. 

Dr. Andre Larochelle
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • hematopoietic stem cell
  • iPSC
  • ESC
  • pluripotent stem cell
  • differentiation
  • hematopoiesis
  • mesoderm
  • gene editing
  • gene therapy
  • cell therapy
  • inherited blood disorder

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Published Papers (6 papers)

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Research

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23 pages, 7202 KiB  
Article
Challenges in Cell Fate Acquisition to Scid-Repopulating Activity from Hemogenic Endothelium of hiPSCs Derived from AML Patients Using Forced Transcription Factor Expression
by Deanna P. Porras, Jennifer C. Reid, Borko Tanasijevic, Diana Golubeva, Allison L. Boyd and Mickie Bhatia
Cells 2022, 11(12), 1915; https://doi.org/10.3390/cells11121915 - 13 Jun 2022
Viewed by 2298
Abstract
The generation of human hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) represents a major goal in regenerative medicine and is believed would follow principles of early development. HSCs arise from a type of endothelial cell called a “hemogenic endothelium” (HE), [...] Read more.
The generation of human hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) represents a major goal in regenerative medicine and is believed would follow principles of early development. HSCs arise from a type of endothelial cell called a “hemogenic endothelium” (HE), and human HSCs are experimentally detected by transplantation into SCID or other immune-deficient mouse recipients, termed SCID-Repopulating Cells (SRC). Recently, SRCs were detected by forced expression of seven transcription factors (TF) (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, and SPI1) in hPSC-derived HE, suggesting these factors are deficient in hPSC differentiation to HEs required to generate HSCs. Here we derived PECAM-1-, Flk-1-, and VE-cadherin-positive endothelial cells that also lack CD45 expression (PFVCD45−) which are solely responsible for hematopoietic output from iPSC lines reprogrammed from AML patients. Using HEs derived from AML patient iPSCs devoid of somatic leukemic aberrations, we sought to generate putative SRCs by the forced expression of 7TFs to model autologous HSC transplantation. The expression of 7TFs in hPSC-derived HE cells from an enhanced hematopoietic progenitor capacity was present in vitro, but failed to acquire SRC activity in vivo. Our findings emphasize the benefits of forced TF expression, along with the continued challenges in developing HSCs for autologous-based therapies from hPSC sources. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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15 pages, 2034 KiB  
Article
Assessment of the Hematopoietic Differentiation Potential of Human Pluripotent Stem Cells in 2D and 3D Culture Systems
by German Atzin Mora-Roldan, Dalia Ramirez-Ramirez, Rosana Pelayo and Karlen Gazarian
Cells 2021, 10(11), 2858; https://doi.org/10.3390/cells10112858 - 23 Oct 2021
Cited by 6 | Viewed by 5219
Abstract
Background. In vitro methods for hematopoietic differentiation of human pluripotent stem cells (hPSC) are a matter of priority for the in-depth research into the mechanisms of early embryogenesis. So-far, published results regarding the generation of hematopoietic cells come from studies using either 2D [...] Read more.
Background. In vitro methods for hematopoietic differentiation of human pluripotent stem cells (hPSC) are a matter of priority for the in-depth research into the mechanisms of early embryogenesis. So-far, published results regarding the generation of hematopoietic cells come from studies using either 2D or 3D culture formats, hence, it is difficult to discern their particular contribution to the development of the concept of a unique in vitro model in close resemblance to in vivo hematopoiesis. Aim of the study. To assess using the same culture conditions and the same time course, the potential of each of these two formats to support differentiation of human pluripotent stem cells to primitive hematopoiesis without exogenous activation of Wnt signaling. Methods. We used in parallel 2D and 3D formats, the same culture environment and assay methods (flow cytometry, IF, qPCR) to investigate stages of commitment and specification of mesodermal, and hemogenic endothelial cells to CD34 hematopoietic cells and evaluated their clonogenic capacity in a CFU system. Results. We show an adequate formation of mesoderm, an efficient commitment to hemogenic endothelium, a higher number of CD34 hematopoietic cells, and colony-forming capacity potential only in the 3D format-supported differentiation. Conclusions. This study shows that the 3D but not the 2D format ensures the induction and realization by endogenous mechanisms of human pluripotent stem cells’ intrinsic differentiation program to primitive hematopoietic cells. We propose that the 3D format provides an adequate level of upregulation of the endogenous Wnt/β-catenin signaling. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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Review

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30 pages, 1747 KiB  
Review
De Novo Generation of Human Hematopoietic Stem Cells from Pluripotent Stem Cells for Cellular Therapy
by Jianyi Ding, Yongqin Li and Andre Larochelle
Cells 2023, 12(2), 321; https://doi.org/10.3390/cells12020321 - 14 Jan 2023
Cited by 8 | Viewed by 3943
Abstract
The ability to manufacture human hematopoietic stem cells (HSCs) in the laboratory holds enormous promise for cellular therapy of human blood diseases. Several differentiation protocols have been developed to facilitate the emergence of HSCs from human pluripotent stem cells (PSCs). Most approaches employ [...] Read more.
The ability to manufacture human hematopoietic stem cells (HSCs) in the laboratory holds enormous promise for cellular therapy of human blood diseases. Several differentiation protocols have been developed to facilitate the emergence of HSCs from human pluripotent stem cells (PSCs). Most approaches employ a stepwise addition of cytokines and morphogens to recapitulate the natural developmental process. However, these protocols globally lack clinical relevance and uniformly induce PSCs to produce hematopoietic progenitors with embryonic features and limited engraftment and differentiation capabilities. This review examines how key intrinsic cues and extrinsic environmental inputs have been integrated within human PSC differentiation protocols to enhance the emergence of definitive hematopoiesis and how advances in genomics set the stage for imminent breakthroughs in this field. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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16 pages, 1891 KiB  
Review
Hematopoietic Cells from Pluripotent Stem Cells: Hope and Promise for the Treatment of Inherited Blood Disorders
by Ilaria Rao, Laura Crisafulli, Marianna Paulis and Francesca Ficara
Cells 2022, 11(3), 557; https://doi.org/10.3390/cells11030557 - 5 Feb 2022
Cited by 11 | Viewed by 5239
Abstract
Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure [...] Read more.
Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure associated to severe complications; other therapies include red blood cell and platelet transfusions, which are dependent on donor availability. An alternative option is gene therapy, in which the wild-type form of the mutated gene is delivered into autologous hematopoietic stem cells using viral vectors. A more recent therapeutic perspective is gene correction through CRISPR/Cas9-mediated gene editing, that overcomes safety concerns due to insertional mutagenesis and allows correction of base substitutions in large size genes difficult to incorporate into vectors. However, applying this technique to genomic disorders caused by large gene deletions is challenging. Chromosomal transplantation has been proposed as a solution, using a universal source of wild-type chromosomes as donor, and induced pluripotent stem cells (iPSCs) as acceptor. One of the obstacles to be addressed for translating PSC research into clinical practice is the still unsatisfactory differentiation into transplantable hematopoietic stem or mature cells. We provide an overview of the recent progresses in this field and discuss challenges and potential of iPSC-based therapies for the treatment of inherited blood disorders. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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19 pages, 1730 KiB  
Review
Notch Signaling in HSC Emergence: When, Why and How
by Roshana Thambyrajah and Anna Bigas
Cells 2022, 11(3), 358; https://doi.org/10.3390/cells11030358 - 21 Jan 2022
Cited by 11 | Viewed by 5501
Abstract
The hematopoietic stem cell (HSC) sustains blood homeostasis throughout life in vertebrates. During embryonic development, HSCs emerge from the aorta-gonads and mesonephros (AGM) region along with hematopoietic progenitors within hematopoietic clusters which are found in the dorsal aorta, the main arterial vessel. Notch [...] Read more.
The hematopoietic stem cell (HSC) sustains blood homeostasis throughout life in vertebrates. During embryonic development, HSCs emerge from the aorta-gonads and mesonephros (AGM) region along with hematopoietic progenitors within hematopoietic clusters which are found in the dorsal aorta, the main arterial vessel. Notch signaling, which is essential for arterial specification of the aorta, is also crucial in hematopoietic development and HSC activity. In this review, we will present and discuss the evidence that we have for Notch activity in hematopoietic cell fate specification and the crosstalk with the endothelial and arterial lineage. The core hematopoietic program is conserved across vertebrates and here we review studies conducted using different models of vertebrate hematopoiesis, including zebrafish, mouse and in vitro differentiated Embryonic stem cells. To fulfill the goal of engineering HSCs in vitro, we need to understand the molecular processes that modulate Notch signaling during HSC emergence in a temporal and spatial context. Here, we review relevant contributions from different model systems that are required to specify precursors of HSC and HSC activity through Notch interactions at different stages of development. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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11 pages, 2138 KiB  
Review
Single-Cell Approaches to Deconvolute the Development of HSCs
by Yang Xiang and Ryohichi Sugimura
Cells 2021, 10(11), 2876; https://doi.org/10.3390/cells10112876 - 25 Oct 2021
Cited by 1 | Viewed by 3970
Abstract
Hematopoietic stem cells (HSCs) play a core role in blood development. The ability to efficiently produce HSCs from various pluripotent stem cell sources is the Holy Grail in the hematology field. However, in vitro or in vivo HSC production remains low, which may [...] Read more.
Hematopoietic stem cells (HSCs) play a core role in blood development. The ability to efficiently produce HSCs from various pluripotent stem cell sources is the Holy Grail in the hematology field. However, in vitro or in vivo HSC production remains low, which may be attributable to the lack of understanding of hematopoiesis. Here, we review the recent progress in this area and introduce advanced technologies, such as single-cell RNA-seq, spatial transcriptomics, and molecular barcoding, which may help to acquire missing information about HSC generation. We finally discuss unresolved questions, the answers to which may be conducive to HSC production, providing a promising path toward HSC-based immunotherapies. Full article
(This article belongs to the Special Issue Generation of Hematopoietic Stem/Progenitor Cells from Pluripotent Stem Cells for Cellular Therapy)
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