Sequential cellular niches control the generation of enucleated erythrocytes from human pluripotent stem cells

Shen, Jun; Zhu, Yaoyao; Lyu, Cuicui; Feng, Zicen; Lyu, Shuzhen; Zhao, Yong; Hoyle, Dixie L.; Ji, Guangzhen; Miao, Weimin; Zhang, Xiaobing; Cheng, Linzhao; Cheng, Tao; Wang, Zack Z.

doi:10.3324/haematol.2018.211664

Cited by 19 publications

(26 citation statements)

References 15 publications

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“…Reprogramming of somatic cells to the pluripotent state has been suggested as an alternative source and a novel opportunity for patient-specific stem cell-based therapies, modeling of RBCs diseases, and drug testing [ 155 ]. Previous studies have shown that human iPSCs can give rise to erythroid cells, while in vitro derivation and maintenance of enucleated erythrocytes have still been challenging [ 86 ]. Also, many hurdles such as reprogramming without retroviruses, large scale and cost-effective production of iPSC-derived enucleated RBCs, and defined xenogenic-free conditions remain to be improved before human iPSC-based therapy [ 156 , 157 ].…”

Section: Discussionmentioning

confidence: 99%

“…Many attempts have been made previously to achieve human iPSC-derived RBCs under conventional culture methods with SCF, EPO, VEGF, insulin-like growth factor I (IGF-1), dexamethasone (glucocorticoid receptor agonist), ITS (insulin, transferrin, and selenium), TPO, FLT3, BMP4, IL-3, IL-6, and EPO (Table 1 ). However, an ideal culture condition for human iPSC-derived RBCs should be able to generate large numbers of functional enucleated erythrocytes [ 31 , 86 ]. Feeder cells as a major cellular component have been found to enhance hematopoiesis from human iPSCs [ 81 , 82 ].…”

Section: Introductionmentioning

confidence: 99%

“…Feeder cells as a major cellular component have been found to enhance hematopoiesis from human iPSCs [ 81 , 82 ]. It has been shown that OP9 feeder cells as a mouse bone marrow stromal cell line may enhance the hematopoietic differentiation of human iPSCs [ 86 ]. Also, C3H10T1/2 feeder cells have the capacity to stimulate the hematopoietic differentiation of human iPSCs [ 38 , 87 ].…”

Section: Introductionmentioning

confidence: 99%

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Differentiation of human induced pluripotent stem cells into erythroid cells

et al. 2020

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During the last years, several strategies have been made to obtain mature erythrocytes or red blood cells (RBC) from the bone marrow or umbilical cord blood (UCB). However, UCB-derived hematopoietic stem cells (HSC) are a limited source and in vitro large-scale expansion of RBC from HSC remains problematic. One promising alternative can be human pluripotent stem cells (PSCs) that provide an unlimited source of cells. Human PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are self-renewing progenitors that can be differentiated to lineages of ectoderm, mesoderm, and endoderm. Several previous studies have revealed that human ESCs can differentiate into functional oxygen-carrying erythrocytes; however, the ex vivo expansion of human ESC-derived RBC is subjected to ethical concerns. Human iPSCs can be a suitable therapeutic choice for the in vitro/ex vivo manufacture of RBCs. Reprogramming of human somatic cells through the ectopic expression of the transcription factors (OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG) has provided a new avenue for disease modeling and regenerative medicine. Various techniques have been developed to generate enucleated RBCs from human iPSCs. The in vitro production of human iPSC-derived RBCs can be an alternative treatment option for patients with blood disorders. In this review, we focused on the generation of human iPSC-derived erythrocytes to present an overview of the current status and applications of this field.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differentiation of human induced pluripotent stem cells into erythroid cells

et al. 2020

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“…To gain insights into the genetic regulation of hematopoietic development, we performed single-cell transcriptional profiling of human embryonic stem cells (H1 hESCs) navigating from pluripotency through the stage-specific transitions of hematopoietic differentiation using 10× Genomics Chromium platform. A monolayer-based, chemically defined culture was modified as an efficient method to direct pluripotent cell differentiation toward the endothelial and hematopoietic (EC-HC) lineages as previously described (23)(24)(25). Mesoderm progenitors (T-GFP + ), CD34 + KDR + CD144 + ECs, and CD43 + HPCs were identified at days 2, 4, and 6 of differentiation, respectively (fig.…”

Section: Scrna-seq Analysis Of Hematopoietic Directed Differentiationmentioning

confidence: 99%

Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

Shen

Zhang

et al. 2021

Sci. Adv.

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Hematopoietic differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic cell and gene regulatory networks but often generates blood cells that lack natural function. Here, we performed extensive single-cell transcriptomic analyses to map fate choices and gene expression patterns during hematopoietic differentiation of hPSCs and showed that oxidative metabolism was dysregulated during in vitro directed differentiation. Applying hypoxic conditions at the stage of endothelial-to-hematopoietic transition in vitro effectively promoted the development of arterial specification programs that governed the generation of hematopoietic progenitor cells (HPCs) with functional T cell potential. Following engineered expression of the anti-CD19 chimeric antigen receptor, the T cells generated from arterial endothelium-primed HPCs inhibited tumor growth both in vitro and in vivo. Collectively, our study provides benchmark datasets as a resource to further understand the origins of human hematopoiesis and represents an advance in guiding in vitro generation of functional T cells for clinical applications.

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“…RBC regeneration in vitro has been an important research direction in the blood research field for many years [3,4]. In the current study, the primitive materials that can be used for RBC regeneration are mainly cord blood hematopoietic stem cells (HSCs) [5], embryonic stem cells (ESCs) [6,7], and induced pluripotent stem cells (iPSCs) [6,8]. The regeneration technology of cord blood HSCs is relatively mature; however, some problems come with this technology, such as difficulty obtaining materials, significant differences among individuals, the high price of this technology, and ESCs are subject to ethical restrictions [9].…”

Section: Introductionmentioning

confidence: 99%

Mapping Human Pluripotent Stem Cell-Derived Erythroid Differentiation by Single-Cell Transcriptome Analysis

Xin

Zhang

Gong

et al. 2019

Preprint

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36There is currently an imbalance between the supply and demand of functional red 37 blood cells (RBCs) in clinical applications, and this imbalance can be addressed by 38regenerating RBCs with a variety of in vitro methods. Induced pluripotent stem cells 39 (iPSCs) can address the low supply of cord blood and the ethical issues in embryonic 40 stem cell research and provide a promising strategy to eliminate immune rejection. 41However, no complete single-cell level differentiation pathway exists for the 42 iPSC-derived RBC differentiation system. In this study, we used iPSC line BC1 to 43 establish an RBC regeneration system and used the 10× Genomics single-cell 44 transcriptome platform to map the cell lineage and differentiation trajectories on day 45 14 (D14) of the regeneration system. We found iPSC differentiation was not 46 synchronized during embryoid body (EB) culture, and the D14 cells in the system 47 mainly consisted of mesodermal and various blood cells, similar to yolk sac 48 hematopoiesis. During asynchronous EB differentiation, iPSCs undergo three 49 bifurcations before they enter erythroid differentiation, and the driver genes of each 50 bifurcation were identified. The key roles of cell adhesion and estradiol in RBC 51 regeneration were observed. This study provides systematically theoretical guidance 52 for the optimization of the iPSC-derived RBC differentiation system. 53 54

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Sequential cellular niches control the generation of enucleated erythrocytes from human pluripotent stem cells

Cited by 19 publications

References 15 publications

Differentiation of human induced pluripotent stem cells into erythroid cells

Differentiation of human induced pluripotent stem cells into erythroid cells

Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

Mapping Human Pluripotent Stem Cell-Derived Erythroid Differentiation by Single-Cell Transcriptome Analysis

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