Evaluation of Stem Cell-Derived Red Blood Cells as a Transfusion Product Using a Novel Animal Model

Abstract

Reliance on volunteer blood donors can lead to transfusion product shortages, and current liquid storage of red blood cells (RBCs) is associated with biochemical changes over time, known as ‘the storage lesion’. Thus, there is a need for alternative sources of transfusable RBCs to supplement conventional blood donations. Extracorporeal production of stem cell-derived RBCs (stemRBCs) is a potential and yet untapped source of fresh, transfusable RBCs. A number of groups have attempted RBC differentiation from CD34+ cells. However, it is still unclear whether these stemRBCs could eventually be effective substitutes for traditional RBCs due to potential differences in oxygen carrying capacity, viability, deformability, and other critical parameters. We have generated ex vivo stemRBCs from primary human cord blood CD34+ cells and compared them to donor-derived RBCs based on a number of in vitro parameters. In vivo, we assessed stemRBC circulation kinetics in an animal model of transfusion and oxygen delivery in a mouse model of exercise performance. Our novel, chronically anemic, SCID mouse model can evaluate the potential of stemRBCs to deliver oxygen to tissues (muscle) under resting and exercise-induced hypoxic conditions. Based on our data, stem cell-derived RBCs have a similar biochemical profile compared to donor-derived RBCs. While certain key differences remain between donor-derived RBCs and stemRBCs, the ability of stemRBCs to deliver oxygen in a living organism provides support for further development as a transfusion product.

Evaluation of renal oxygen homeostasis in a preclinical animal model to elucidate difference in blood quality after transfusion

“…We acknowledge the limitations of this study, which include the use of surrogate species RBCs, which may differ from human in response to processing and in this case storage . However, to our knowledge only nonhuman primates can be directly transfused with human RBCs, otherwise immune suppression models are required . In each case different limitations arise.…”

“…28,29 However, to our knowledge only nonhuman primates can be directly transfused with human RBCs, 30 otherwise immune suppression models are required. 31,32 In each case different limitations arise. We also recognize that our measurements of O 2 homeostasis are not quantitative for intracellular or tPO 2 .…”

The Shape Shifting Story of Reticulocyte Maturation

“…Second challenge of red blood cells production is the quality of product. Existing laboratory culture systems give rise to reticulocytes of different stages of maturity using various culture systems and starting material depending or not depending on co-culture with specific stromal cells ( Migliaccio et al, 2002 , 2010 ; Giarratana et al, 2005 ; Leberbauer et al, 2005 ; Miharada et al, 2006 ; van den Akker et al, 2010a ; Shah et al, 2016 ; Trakarnsanga et al, 2017 ). Reticulocytes are immature red blood cells that lost their nucleus but still retain residual RNA.…”

Purifying stem cell‐derived red blood cells: a high‐throughput label‐free downstream processing strategy based on microfluidic spiral inertial separation and membrane filtration

“…The membrane filtration step requires further optimization and development, since in this study, dead‐end filtration, which is prone to membrane fouling, led to the separation efficiency of 30–50% of enucleated cells. Shah et al (2016) reported a positive evaluation of CB CD34+ derived mRBC as transfusion product (Shah et al, 2016), using their novel animal model to assess the potential of mRBCs to deliver oxygen to muscle tissues. To deplete undifferentiated nucleated cells before transfusion, they used a nonwoven fabric filter (Tao, Xia, Cao, & Gao, 2011).…”