Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

Abstract

Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells.

Figure 1

Schematic representations of hematopoietic development from in vivo and in vitro models. Both human and mouse in vitro models have been established for hematopoietic differentiation in a defined culture system from embryonic stem (ES) and adult cell-derived induced pluripotent stem (iPS) cells. For the in vivo model, the mouse inner cell mass undergoes differentiation, later forming the yolk sac, which generates mesodermal cells and induces hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs) and mature hematopoietic cells (HCs). Successfully generated HSCs from both in vitro and in vivo models might be applied to HSC transplantation for hematopoietic disorders. Further differentiation of HSC in a cytokine-defined culture system produces hematopoietic cells for hematopoietic cell transfusion. Thorough understanding of molecular mechanism on these models will be beneficial for both drug screening as well as the mechanism of hematopoiesis development.

Figure 2

Schematic representations of induction systems and criteria for successful hematopoietic development. Both mouse and human embryonic stem (ES)/induced pluripotent stem (iPS) cells can be differentiated into hematopoietic cells (HCs) from mesodermal cells with three approaches: embryoid body formation, feeder cell co-culture and extracellular matrix-coated culture. Hematopoietic stem cells and differentiated HCs must be tested and screened both in vitro and in vivo before being applied to patients.

Figure 3

Schematic representations of each hematopoietic cell lineage with respect to their applications and disease-treatment potentials. After pre-hematopoietic stem cells (HSCs) commit to mature HSCs, multipotent progenitor (MPP) cells are generated with the potential to further differentiate into two major lineages: common myeloid progenitor (CMP) and common lymphoid progenitor (CLP). In myeloid lineage, CMP will further divide into megakaryocyte–erythroid progenitor (MEP) and granulocyte/monocyte progenitor (GMP), finally committing to mature blood cells comprising of erythrocytes, megakaryocyte → platelets, monocyte → macrophages and granulocytes (neutrophils, eosinophils, basophils). In lymphoid lineage, CLP will further differentiate into B-cell and T-cell and natural killer (NK) cell progenitors, with a final commitment to mature B cells, T cells and NK cells. Each lineage serves as a powerful regenerative tool, including treatment for hemoglobinopathies (anemia, thalassemia), thrombocytopenia, leukocyte and immunodeficient-related diseases. This model might also clarify the molecular mechanism behind certain disorders, for example atherosclerotic lesions.