2022 May 24

In vitro myelopoiesis from iPSCs resembles human early blood formation and opens the door to new therapeutic opportunities for cancer and inflammatory diseases

A team coordinated by the Wellcome Sanger Institute and the Josep Carreras Leukaemia Research Institute has generated a robust molecular map of the differentiation of human induced pluripotent stem cells (iPSC) into macrophages, which faithfully recapitulates the early stages of myeloid differentiation. This roadmap of early myeloid differentiation represents an essential step towards better understanding the initial stages of hematopoiesis, which are largely unexplored in humans, and will open up new cell-based therapeutic opportunities.

The myeloid lineage comprises cells as different as red blood cells, platelets, macrophages and dendritic cells. The latter are of particular interest due to its disease fighting capabilities. In the dawn of the cellular therapies, like the CAR-Ts and their derivatives, the mass production of immune cells able to control inflammation and immune response is of great interest.

The downside is that myeloid differentiation, from the early progenitors to the mature cells, is not completely understood in humans. In the new research, published at the top journal Nature Communications, researchers profiled the transcriptome and epigenome of more than 400,000 induced pluripotent stem cells (iPSC) progressing into macrophages by using single-cell techniques, and applied machine learning tools to map them to developmental in vivo atlases, identifying the key intermediate progenitors produced and their molecular identities, such as their particular transcription factor networks.

The results of the study, supervised by Dr. Damiana Álvarez-Errico, leader of the Josep Carreras Institute’s Genomics Unit, show that iPSC-macrophage differentiation in vitro resembles very much fetal in vivo myelopoiesis in humans, with the production of a wide range of cells from the endoderm lineage to the innate immune cells. This is a valuable knowledge to fully understand the early stages of myelopoiesis in humans, that would not be accessible otherwise.

Furthermore, the researchers adapted the standard Wilgenburg protocol to the production of mature macrophages and type-2 dendritic cells, capable of fighting against inflammatory diseases and infiltrate into tumors, opening a new line of research to understand their role in disease and how could they be used as immunotherapeutic tools.

Reference Article:

Alsinet, C., Primo, M.N., Lorenzi, V. et al. “Robust temporal map of human in vitro myelopoiesis using single-cell genomics”. 

Nat Commun 13, 2885 (2022). https://doi.org/10.1038/s41467-022-30557-4