Induced Pluripotent Stem Cell-Derived Red Blood Cells and Platelet Concentrates: From Bench to Bedside

Abstract

Red blood cells and platelets are anucleate blood components indispensable for oxygen delivery and hemostasis, respectively. Derivation of these blood elements from induced pluripotent stem (iPS) cells has the potential to develop blood donor-independent and genetic manipulation-prone products to complement or replace current transfusion banking, also minimizing the risk of alloimmunization. While the production of erythrocytes from iPS cells has challenges to overcome, such as differentiation into adult-type phenotype that functions properly after transfusion, platelet products are qualitatively and quantitatively approaching a clinically-applicable level owing to advances in expandable megakaryocyte (MK) lines, platelet-producing bioreactors, and novel reagents. Guidelines that assure the quality of iPS cells-derived blood products for clinical application represent a novel challenge for regulatory agencies. Considering the minimal risk of tumorigenicity and the expected significant demand of such products, ex vivo production of iPS-derived blood components can pave the way for iPS translation into the clinic.

The Shape Shifting Story of Reticulocyte Maturation

“…High enucleation rates have been described for in vitro culture systems that initiate from cord blood, fetal or adult CD34+ hematopoietic stem and progenitor cells ( Leberbauer et al, 2005 ; van den Akker et al, 2010a ; Giarratana et al, 2011 ). In contrast, enucleation is generally poor in immortalized cell lines and erythroid cells derived from induced pluripotent stem cells ( Lapillonne et al, 2010 ; Kurita et al, 2013 ; Trakarnsanga et al, 2017 ) [reviewed by ( Focosi and Amabile, 2017 )]. Resolving the fine details of the enucleation process and events leading up to enucleation may facilitate and improve the production of erythrocytes from these immortal sources.…”

A β1-tubulin–based megakaryocyte maturation reporter system identifies novel drugs that promote platelet production

“…The establishment of imMKCLs represents an important advance toward generating large numbers of iPSC-derived platelets ex vivo, but the low PLP yield and requirement of mouse somatic feeder cells are major hurdles that must be overcome before clinical realization. 33 In the current study, we present experimental and practical details of a b1-tubulin-Venus reporter line that promises to accelerate our search for optimal conditions for imMKCL Compounds/M By screening .5000 compounds, a series of candidates were identified from distinct categories that were not reported to promote MK maturation and PLP production (Figure 2). Wnt-C59 and TCS 359 are known inhibitors of WNT signaling and FLT3, respectively; however, other compounds exhibiting similar inhibitor effects on WNT and FLT3 signaling did not show similar effects in the reporter cell line ( Figure 4A).…”

Innovations in Human Stem Cell Research: A Holy Grail for Regenerative Medicine

“…A challenge for the PSC or iPSC differentiation, as also mentioned above in the iPSC-derived MNs, is that the PSC-derived cells tend to be immature. This is indeed the major limitation for translating iPSC-derived red blood cells into the clinic [25]. In 2008, Lu et al reported differentiation of human ES cells into functional oxygencarrying erythrocytes on a large scale with up to 60% enucleation rate [26].…”