Department of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands.
College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge UB8 3PH, U.K.
Emerg Top Life Sci. 2023 Dec 18;7(4):439-454. doi: 10.1042/ETLS20230091.
Haematopoietic stem cells (HSCs) are the most extensively studied adult stem cells. Yet, six decades after their first description, reproducible and translatable generation of HSC in vitro remains an unmet challenge. HSC production in vitro is confounded by the multi-stage nature of blood production during development. Specification of HSC is a late event in embryonic blood production and depends on physical and chemical cues which remain incompletely characterised. The precise molecular composition of the HSC themselves is incompletely understood, limiting approaches to track their origin in situ in the appropriate cellular, chemical and mechanical context. Embryonic material at the point of HSC emergence is limiting, highlighting the need for an in vitro model of embryonic haematopoietic development in which current knowledge gaps can be addressed and exploited to enable HSC production. Gastruloids are pluripotent stem cell-derived 3-dimensional (3D) cellular aggregates which recapitulate developmental events in gastrulation and early organogenesis with spatial and temporal precision. Gastruloids self-organise multi-tissue structures upon minimal and controlled external cues, and are amenable to live imaging, screening, scaling and physicochemical manipulation to understand and translate tissue formation. In this review, we consider the haematopoietic potential of gastruloids and review early strategies to enhance blood progenitor and HSC production. We highlight possible strategies to achieve HSC production from gastruloids, and discuss the potential of gastruloid systems in illuminating current knowledge gaps in HSC specification.
造血干细胞(HSCs)是研究最为广泛的成人干细胞。然而,在首次描述它们的 60 年后,体外可重复且可转化的 HSC 生成仍然是一个未满足的挑战。体外 HSC 的生成受到发育过程中血液生成的多阶段性质的影响。HSC 的特化是胚胎血液生成中的晚期事件,取决于物理和化学线索,这些线索仍未完全描述。HSC 本身的确切分子组成尚不完全清楚,限制了在适当的细胞、化学和机械背景下追踪其起源的方法。在 HSC 出现点的胚胎材料是有限的,这突出表明需要一种体外胚胎造血发育模型,以解决当前的知识空白,并利用这些知识空白来实现 HSC 的生成。原肠胚类器官是多能干细胞衍生的 3 维(3D)细胞聚集体,可精确地重现原肠胚形成和早期器官发生中的发育事件。原肠胚类器官在最小和受控的外部线索下自我组织多组织结构,并且易于进行活细胞成像、筛选、扩展和物理化学操作,以理解和转化组织形成。在这篇综述中,我们考虑了原肠胚类器官的造血潜力,并回顾了早期增强血液祖细胞和 HSC 生成的策略。我们强调了从原肠胚类器官实现 HSC 生成的可能策略,并讨论了原肠胚类器官系统在阐明 HSC 特化当前知识空白方面的潜力。