Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell

Li, Jiaxing; Wang, Xiao; Ding, Jiayu; Zhu, Yasheng; Min, Wenjian; Kuang, Wenbing; Yuan, Kai; Sun, Chengliang; Yang, Peng

doi:10.1016/j.apsb.2021.12.006

Cited by 13 publications

(7 citation statements)

References 176 publications

(326 reference statements)

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“…To maintain LT-HSCs ex vivo, there needs to be defined conditions which allow activation and proliferation without inducing differentiation to ST-HSC and subsequent committed progenitors 4 . This has proven to be impossible to achieve in a heterogenous BM cell population, especially when a single parameter, such as one signalling pathway, is targeted with small molecules 8 . Multiple cell types also interact in the BM and co-operate with each other through cell-cell adhesion and paracrine signals, such as mesenchymal stromal cells (MSCs) and perivascular stromal cells (PerSCs) [12][13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, maintaining and, ultimately, expanding LT-HSCs ex vivo has become a major focus of research. Several culture systems, such as Dexter cultures 6 , and the use of cytokines 7 and small molecules 8 , have successfully expanded heterogenous CD34+ HSCs in vitro but with the concomitant loss of naïve LT-HSCs, producing populations with clonal heterogeneity 9 . Subsequent transplantation studies and phase I/II clinical trials (with e.g.…”

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confidence: 99%

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Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells

Donnelly

Ross

Xiao

et al. 2022

Preprint

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Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via allogeneic stem cell transplantation (alloSCT), to engraft and repopulate the blood system. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs (ST-HSC) and progenitor populations at the expense of naïve LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs or pericytes). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal ability and without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells

Donnelly

Ross

Xiao

et al. 2022

Preprint

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“…Cells 2023, 12, x 2 of 31 However, safe, effective and clinically feasible expansion methodologies remain unavailable. The current state of ex vivo HSC expansion for clinical applications has been reviewed elsewhere [1][2][3]. De novo generation of HSCs provides an alternative tool for the development of cell-based therapies, and offers additional applications for disease modeling and drug testing when primary cells from patients are limited [4].…”

Section: Approaches To Increase Hsc Availabilitymentioning

confidence: 99%

De Novo Generation of Human Hematopoietic Stem Cells from Pluripotent Stem Cells for Cellular Therapy

Ding

Larochelle

2023

Cells

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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.

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“…In the context of autologous gene therapy applications, sufficient functional HSCs from bone marrow (BM) or mobilized peripheral blood (MPB) cell collections are also commonly unavailable in patients with impaired hematopoiesis, such as BM failure syndromes and chronic inflammatory disorders [1][2][3]. Current protocols to augment cell dose by expansion of human HSCs ex vivo are inefficient [4][5][6]. De novo generation of human HSPCs is a tractable alternative for the development of cell-based therapies when primary HSPCs are limited.…”

Section: Introductionmentioning

confidence: 99%

Modulation of WNT, Activin/Nodal and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation

Ding

Araki

et al. 2023

Preprint

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Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecule regulators CHIR99021, SB431542 and LY294002, respectively, and measured the impact on hematoendothelial formation in culture. Manipulation of these pathways provided a synergy sufficient to enhance formation of arterial hemogenic endothelium (HE) relative to control culture conditions. Importantly, this approach significantly increased production of human HSPCs with self-renewal and multilineage differentiation properties, as well as phenotypic and molecular evidence of progressive maturation in culture. Together, these findings provide a stepwise improvement in human iPSC differentiation protocols and offer a framework for manipulating intrinsic cellular cues to enable de novo generation of human HSPCs with functionality in vivo.

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Development and clinical advancement of small molecules for ex vivo expansion of hematopoietic stem cell

Cited by 13 publications

References 176 publications

Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells

Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells

De Novo Generation of Human Hematopoietic Stem Cells from Pluripotent Stem Cells for Cellular Therapy

Modulation of WNT, Activin/Nodal and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation

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