U.S. Department of Health and Human Services

Revving up human red blood cell production

A recent study demonstrates that “turning off” a single gene significantly increased production of human red blood cells (RBCs) in the laboratory.  The mechanisms controlling the transition from embryonic stem cells (ESCs) or early stage (progenitor) blood cells to mature RBCs are not well understood, but such knowledge could provide critical insight into how to produce blood cells in the laboratory.  

While characterizing samples obtained from 4,678 volunteers, researchers discovered 11 rare mutations in the SH2B3 gene associated with higher hemoglobin and hematocrit levels.  Hemoglobin carries oxygen in RBCs from the lungs to the rest of the body, and the hematocrit measures the percentage of the blood that consists of RBCs.  Thus, people who have a rare SH2B3 mutation have higher levels of RBCs in their blood.    

To confirm that the SH2B3 genetic mutation was responsible for the increased RBC production, two different genetic approaches were used to essentially block the function of the gene in human ESCs and progenitor cells, which can mature to become various types of blood cells.  The maturation of human ESCs and progenitor cells into RBCs is accomplished in the laboratory by the addition of a cocktail containing various factors identified from previous research.  In the first approach, they used a technique called RNA interference to prevent cells from making the protein encoded by the SH2B3 gene by disrupting a key intermediate in the protein-making process, a copy of the gene made of RNA.  The scientists found that this approach successfully increased RBC production by at least 3-fold.  The increased RBC production was due to both increased maturation and increased production, and the newly produced RBCs appeared to have similar size and shape to natural RBCs.  In the second approach, the SH2B3 gene was inactivated in a line of human ESCs by the CRISPR/Cas9 system, which enables the gene’s DNA to be edited with unprecedented precision.  (The NIH supports research using human ESCs within the NIH Guidelines for Human Stem Cell Research.)  The results of this set of experiments showed that ESCs lacking a functional SH2B3 gene produced approximately 3-fold more RBCs than human ESCs having the intact gene.  Although the RNA interference method would be difficult to scale-up to produce sufficient quantity of RBCs for clinical use, the CRISPR/Cas9 system could permanently shut-off the SH2B3 gene in a renewable cell line, which could help enable larger-scale production of blood cells.  Thus, the results of two different genetic approaches identify the SH2B3 gene as having a mechanistic role in the ability of stem and progenitor blood cells to develop into RBCs in the laboratory. 

This newly acquired knowledge may contribute to future efforts to improve RBC production for medical applications such as replacement therapy during acute blood loss as a result of trauma or surgical procedures.  This research may also lay the foundation to produce cells of rare blood types for people who need very specific types of blood not available via donated blood resources.

Giani FC, Fiorini C, Wakabayashi A, Ludwig LS, Salem RM, Jobaliya CD, Regan SN, Ulirsch JC, Liang G, Steinberg-Shemer O, Guo MH, Esko T, Tong W, Brugnara C, Hirschhorn JN, Weiss MJ, Zon LI, Chou ST, French DL, Musunuru K, and Sankaran VG. Targeted application of human genetic variation can improve red blood cell production from stem cells. Cell Stem Cell 18: 73-78, 2016.