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抗坏血酸支持从循环造血干细胞体外生成浆细胞样树突状细胞。

Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells.

作者信息

Laustsen Anders, van der Sluis Renée M, Gris-Oliver Albert, Hernández Sabina Sánchez, Cemalovic Ena, Tang Hai Q, Pedersen Lars Henning, Uldbjerg Niels, Jakobsen Martin R, Bak Rasmus O

机构信息

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark.

出版信息

Elife. 2021 Sep 2;10:e65528. doi: 10.7554/eLife.65528.

DOI:10.7554/eLife.65528
PMID:34473049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8445615/
Abstract

Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole-blood HSPCs, and these cells display a pDC phenotype and function. Using GMP-compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways, suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood and lays the foundation for investigating HSPC-pDCs for cell-based immunotherapy.

摘要

浆细胞样树突状细胞（pDCs）是一种具有多种功能的罕见免疫细胞类型，但其作为基于细胞的免疫疗法的潜在用途受到从血液中可提取的细胞数量稀少的挑战。在此，我们系统地研究了从造血干细胞和祖细胞（HSPCs）生成pDCs的培养参数。通过优化条件并结合HSPC预扩增的实施，我们从100,000个脐带血来源的HSPCs开始，平均生成了4.65亿个HSPC来源的pDCs（HSPC-pDCs）。此外，我们证明该方案允许从全血HSPCs生成HSPC-pDCs，并且这些细胞表现出pDC表型和功能。使用符合GMP标准的培养基，我们观察到TLR7/9反应显著丧失，补充抗坏血酸可挽救这种情况。抗坏血酸诱导与pDC特异性固有免疫途径相关的转录特征，表明抗坏血酸对pDC功能具有未描述的作用。这构成了从全血生成pDCs的首个方案，并为研究用于基于细胞的免疫疗法的HSPC-pDCs奠定了基础。

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