Current Advances in Red Blood Cell Generation Using Stem Cells from Diverse Sources

Abstract

Blood transfusions hold an indispensable part in the modern healthcare system. Up to date, the blood supply is largely dependent on donations. Unfortunately, collecting the clinical-grade blood products has become a challenging mission due to accelerated population aging, which not only increases the need for blood transfusions but also decreases the number of healthy donors. Moreover, individuals with severe hematological abnormalities or rare blood phenotypes need alternative therapeutic approaches instead of conventional blood transfusion. In these aspects, the concept ofin vitro/ex vivoproduction of blood cells has been emerging and many attempts have been focused on manufacturing mature erythrocytes, so-called red blood cells (RBCs), the most common and important component among the blood derivatives. In this review, we provide a general overview regarding the current strategies for generating RBCs from various stem cell sources including pluripotent stem cells (PSCs) as well as circulating blood stem cells and the remaining challenges that must be overcome prior to their practical application.

Trends and targets of various types of stem cell derived transfusable RBC substitution therapy: Obstacles that need to be converted to opportunity

“…For example, an anemic mouse is most appropriate to study the oxygen delivery of cultured RBCs, whereas a deeply immunodeficient mouse is better suited for studies that question the survival of transplanted cells [ 7 ]. Clearly, human trials are far more complicated, and to date, there is only one report of testing manufactured RBCs on a single human recipient [ [8] , [9] , [10] , [11] , [12] , [13] ].…”

“…The ability of those cells to promote ex-vivo erythropoiesis has been studied by many research teams. The protocols include addition of specific combinations of growth factors to the cell culture medium in a sequential fashion [ 9 , 10 , 15 ].The role played by MSCs and other cell types from the BM microenvironment has been investigated in several reports [ 14 ].…”

“…The utilization of circulating HSCs from the PB is challenging, since it is easier and less labor intensive than BM. HSC can be collected either in a steady state condition or after G-CSF priming [ [10] , [11] , [12] ]. Researchers have developed an in-vitro RBCs production protocol from PB and proved the therapeutic potential of generated RBCs both in the preclinical and clinical settings [ 18 ].…”

“…The ability of hESCs to differentiate into haematopoietic cells and thus, to the erythroid cell line, was studied with protocols involving EB formations and a co-culture system [ [9] , [10] , [11] , [12] ]. The stromal cells used in most experiments were derived from non-human cell lines.…”

Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis

“…Our knowledge of human erythropoiesis has been greatly advanced by in vitro differentiation systems in which primary multipotent CD34 + hematopoietic stem cell progenitors (HSPCs) are cultured with defined cytokines and other bioactive components to generate reticulocytes (Seo et al, 2019). Erythropoiesis is controlled by the essential cytokines stem cell factor (SCF) and erythropoietin (EPO), and their cognate receptors c-Kit and EPOR (Broudy, 1997;Ingley, 2012;Nocka et al, 1989;Wu et al, 1997;Wu et al, 1995;Zhang and Lodish, 2008).…”