Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Abstract

Induced pluripotent stem cells (iPSCs) represent a valuable cell source able to give rise to different cell types of the body. Among the various pathways of iPSC differentiation, the differentiation into macrophages is a recently developed and rapidly growing technique. Macrophages play a key role in the control of host homeostasis. Their dysfunction underlies many diseases, including hereditary, infectious, oncological, metabolic and other disorders. Targeting macrophage activity and developing macrophage-based cell therapy represent promising tools for the treatment of many pathological conditions. Macrophages generated from human iPSCs (iMphs) provide great opportunities in these areas. The generation of iMphs is based on a step-wise differentiation of iPSCs into mesoderm, hematopoietic progenitors, myeloid monocyte-like cells and macrophages. The technique allows to obtain standardizable populations of human macrophages from any individual, scale up macrophage production and introduce genetic modifications, which gives significant advantages over the standard source of human macrophages, monocyte-derived macrophages. The spectrum of iMph applications is rapidly growing. iMphs have been successfully used to model hereditary diseases and macrophage-pathogen interactions, as well as to test drugs. iMph use for cell therapy is another promising and rapidly developing area of research. The principles and the details of iMph generation have recently been reviewed. This review systemizes current and prospective iMph applications and discusses the problem of iMph safety and other issues that need to be explored before iMphs become clinically applicable.

‘Off the shelf’ immunotherapies: Generation and application of pluripotent stem cell‐derived immune cells

“…The advantages of PSC-derived macrophages include good scalability, high standardization, unlimited quantities, better modelling of tissue-resident macrophages (TRM), and ease of genetic modifications. [77][78][79] Meanwhile, macrophages derived from disease-specific iPSCs provide a useful platform for elucidating disease pathogenesis, analysing the association of genetic mutations with disease, and screening new drug candidates. 79,80 The differentiation strategies of macrophages from PSCs mainly include co-culture systems based on feeder cells, culture systems based on 3D aggregate structure, and feeder-free monolayer differentiation systems.…”

“…[77][78][79] Meanwhile, macrophages derived from disease-specific iPSCs provide a useful platform for elucidating disease pathogenesis, analysing the association of genetic mutations with disease, and screening new drug candidates. 79,80 The differentiation strategies of macrophages from PSCs mainly include co-culture systems based on feeder cells, culture systems based on 3D aggregate structure, and feeder-free monolayer differentiation systems. The co-culture protocols comprise two major steps: induction of HPC differentiation by coculture of PSCs with feeder cells and directed differentiation of HPCs into macrophages.…”

“…Due to the limited number of methods available for purification and expansion of human macrophages, various approaches have been developed to generate macrophages from PSCs. The advantages of PSC‐derived macrophages include good scalability, high standardization, unlimited quantities, better modelling of tissue‐resident macrophages (TRM), and ease of genetic modifications 77–79 . Meanwhile, macrophages derived from disease‐specific iPSCs provide a useful platform for elucidating disease pathogenesis, analysing the association of genetic mutations with disease, and screening new drug candidates 79,80 …”

“… 77 , 78 , 79 Meanwhile, macrophages derived from disease‐specific iPSCs provide a useful platform for elucidating disease pathogenesis, analysing the association of genetic mutations with disease, and screening new drug candidates. 79 , 80 …”

Macrophages as potential targets in gene therapy for cancer treatment

“…They eliminate pathogens and dead cells through phagocytosis, induce inflammatory responses, mediate immune responses, as well as promote tissue repair and regeneration, and then regulate host homeostasis [1,2]. This plasticity of macrophages can be attributed to their distinct transcriptional profiles in response to changes in the tissue environment, which in turn triggers adaptive morphologic and functional changes in the cells [3,4]. Moreover, the homeostatic functions of macrophages can be disrupted by long-term chronic injuries, such as chronic inflammation and tumor progression [5].…”