Generation of Red Blood Cells from Human Pluripotent Stem Cells—An Update

Abstract

Red blood cell (RBC) transfusion is a lifesaving medical procedure that can treat patients with anemia and hemoglobin disorders. However, the shortage of blood supply and risks of transfusion-transmitted infection and immune incompatibility present a challenge for transfusion. The in vitro generation of RBCs or erythrocytes holds great promise for transfusion medicine and novel cell-based therapies. While hematopoietic stem cells and progenitors derived from peripheral blood, cord blood, and bone marrow can give rise to erythrocytes, the use of human pluripotent stem cells (hPSCs) has also provided an important opportunity to obtain erythrocytes. These hPSCs include both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). As hESCs carry ethical and political controversies, hiPSCs can be a more universal source for RBC generation. In this review, we first discuss the key concepts and mechanisms of erythropoiesis. Thereafter, we summarize different methodologies to differentiate hPSCs into erythrocytes with an emphasis on the key features of human definitive erythroid lineage cells. Finally, we address the current limitations and future directions of clinical applications using hiPSC-derived erythrocytes.

Single-cell mitochondrial variant enrichment resolved clonal tracking and spatial architecture in human embryonic hematopoiesis

“…This indicates that all three clones contributed to fetal erythropoiesis driven by EMP. Solute carrier family 4 member 1 (SLC4A1), the surface marker defines orthoE (P. Huang et al, 2020;Lee et al, 2023), was significantly increased in Ery Clone A2 compared with Clone A0 and Clone A1 Fig. (Fig.…”

Blood pharming: exploring the progress and hurdles in producing in-vitro red blood cells for therapeutic applications

“…Studies have employed adult and CB derived HSCs and hematopoietic progenitor cells (HSPCs) to generate RBCs in vitro (32-34) (see Figure 2). However, the accessibility of HSCs and/or HSPCs derived from adult and CB is limited, and the production of RBCs from these sources is not sustainable (8).…”

“…solution by potentially serving as a plentiful source for RBCs owing to their capacity for self-renewal (35)(36)(37). The process of differentiating RBCs from hPSCs closely mirrors the key stages of erythropoiesis, in which HSCs and HSPCs are committed to generating cells of the erythroid lineage under a tightly regulated microenvironment through growth factors and molecules that mimic the natural phenomenon of erythropoiesis (8).…”

“…Research endeavors focusing on the generation of mRBCs date back to the late 1980s (38-40). Differentiation protocols, involving CD34+ HSPCs, have been developed and comprehensively employed (8,41).…”

“…Concentrated research efforts have pivoted towards using multiple cell sources as starting material, including peripheral blood (PB), cord blood (CB), bone marrow (BM), human adult HSCs, erythroblast progenitor cell lines and iPSCs. Amongst these, iPSCs and erythroblast progenitor cell lines have received prominence due to their unparalleled potential for unlimited expansion of mRBCs proposing a viable and scalable alternative to conventional blood transfusions (8). Several protocols are still under investigation to explore the possibilities of generating transfusion grade mRBCs to overcome the hurdles of scarcity of donors, availability of blood for rare blood types and frequency of transfusions.…”