Dendritic cells derived from pluripotent stem cells: Potential of large scale production

Li, Yan; Liu, Meimei; Yang, Shang‐Tian

doi:10.4252/wjsc.v6.i1.1

Cited by 20 publications

(15 citation statements)

References 86 publications

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“…Several groups generated DC from pluripotent stem cells as a potentially unlimited source of autologous DC [39][40][41][42][43][44][45]. Yet, these iPS/ES cell derived DC exhibited a phenotype similar to inflammatory DC and were not subset specific.…”

Section: Discussionmentioning

confidence: 99%

Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells

et al. 2017

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Human induced pluripotent stem (iPS) cells can differentiate into cells of all three germ layers, including hematopoietic stem cells and their progeny. Interferon regulatory factor 8 (IRF8) is a transcription factor, which acts in hematopoiesis as lineage determining factor for myeloid cells, including dendritic cells (DC). Autosomal recessive or dominant IRF8 mutations occurring in patients cause severe monocytic and DC immunodeficiency. To study IRF8 in human hematopoiesis we generated human IRF82/2 iPS cells and IRF82/2 embryonic stem (ES) cells using RNA guided CRISPR/Cas9n genome editing. Upon induction of hematopoietic differentiation, we demonstrate that IRF8 is dispensable for iPS cell and ES cell differentiation into hemogenic endothelium and for endothelial-to-hematopoietic transition, and thus development of hematopoietic progenitors. We differentiated iPS cell and ES cell derived progenitors into CD1411 cross-presenting cDC1 and CD1c1 classical cDC2 and CD3031 plasmacytoid DC (pDC). We found that IRF8 deficiency compromised cDC1 and pDC development, while cDC2 development was largely unaffected. Additionally, in an unrestricted differentiation regimen, IRF82/2 iPS cells and ES cells exhibited a clear bias toward granulocytes at the expense of monocytes. IRF82/2 DC showed reduced MHC class II expression and were impaired in cytokine responses, migration, and antigen presentation. Taken together, we engineered a human IRF8 knockout model that allows studying molecular mechanisms of human immunodeficiencies in vitro, including the pathophysiology of IRF8 deficient DC. STEM CELLS 2017;35:898-908 SIGNIFICANCE STATEMENTPluripotent stem cells and CRISPR/Cas9n technology are particularly well suited for engineering cells to study the impact of specific factors on cell development, including antigen presenting dendritic cells (DC). So far, DC research was limited to primary cell samples obtained for example, from mice or men. In the mouse system, genetically modified DC are readily obtained by using transgenic, knockout, and knockin mice. In the human system studies with mutated DC relied on patients harboring specific mutations and there was a paucity of techniques for genetic engineering directly in human cells. Induced pluripotent stem (iPS) cell and CRISPR/ Cas9n technology now allow to overcome these limitations. Here, we generated interferon regulatory factor 8 (IRF8) knockout human iPS cells and ES cells, and IRF82/2 DC derived thereof. We show that IRF82/2 cells recapitulate the phenotype of individuals with an IRF8 loss of function mutation. Our IRF82/2 iPS cells and ES cells provide a platform to study IRF8 deficient DC subset specification and DC function independent of donor variation or availability. In summary, our IRF82/2 iPS cells and ES cells represent a valid and powerful model to elucidate mechanisms of human DC development and functional diversity.

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Section: Discussionmentioning

confidence: 99%

Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells

et al. 2017

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“…Both involve a multi-step process utilizing various growth factors such as BMP-4, VEGF, GM-CSF, SCF, Flt3L, and IL-4 at key intervals to induce the differentiation [237]. Most importantly, this novel source of DCs has potential for large-scale production using bioreactors [238], unlike the currently used methods, which are highly dependent on operational quality standards. Most recently, a lentiviral vector was used to transduce hPSCs to express the tumor antigen MART-1.…”

Section: New Dcsmentioning

confidence: 99%

Dendritic cell-based immunotherapy

2016

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Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.

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“…This involves multistep process that uses various growth factors such as BMP-4, VEGF, GM-CSF, SCF, Flt3L, and IL-4 at pre-determined intervals (Senju et al 2010). Most importantly, such DCs can potentially be produced at a large scale using bioreactors (Li et al 2014).…”

Section: Optimization Of Generation and Injection Of Dcsmentioning

confidence: 99%

Plant-derived polysaccharides activate dendritic cell-based anti-cancer immunity

et al. 2018

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Today, cancers pose a major public health burden. Although a myriad of cancer treatments are available, only a few have achieved clinical efficacy. This is partly attributed to cancers capability to evade host immunity by converting dendritic cells (DCs) from potent stimulators to negative modulators of immunity. Dendritic cell-based immunotherapy attempts to resolve this problem by manipulating the functional characteristics of DCs. Plant-derived polysaccharides (PDPs) can stimulate the maturation of DCs conferring on them the capacity to present internalised tumorigenic antigens to naïve T cells and subsequently priming T cells to eliminate tumours. PDPs have been used as immune modulators and later as anti-cancer agents by Traditional Chinese Medicine practitioners for centuries. They are abundant in nature and form a large group of heterogeneous though structurally related macromolecules that exhibit diverse immunological properties. They can induce antigen pulsed DCs to acquire functional characteristics in vitro which can subsequently be re-introduced into cancer patients. They can also be used as adjuvants in DC-based vaccines or independently for their intrinsic anti-tumour activities. Clinically, some in vitro generated DCs have been shown to be both safe and immunogenic although their clinical application is limited in part by unsatisfactory functional maturation as well as impaired migration to draining lymph nodes where T cells reside. We review the relative potencies of individual PDPs to induce both phenotypic and functional maturation in DCs, their relative abilities to activate anti-cancer immunity, the possible mechanisms by which they act and also the challenges surrounding their clinical application.

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Dendritic cells derived from pluripotent stem cells: Potential of large scale production

Cited by 20 publications

References 86 publications

Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells

Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells

Dendritic cell-based immunotherapy

Plant-derived polysaccharides activate dendritic cell-based anti-cancer immunity

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