hiPSC-Derived Glial-enriched Progenitor Therapy for White Matter Stroke

Review of “Reliable generation of glial enriched progenitors from human fibroblast-derived iPSCs” from Stem Cell Research by Stuart P. Atkinson

Previous research from the group of William E. Lowry and S. Thomas Carmichael (University of California, Los Angeles, USA) described a strategy to bias human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) towards an astrocytic fate to create a population of glial-enriched progenitors [1-3]. hiPSC-derived glial-enriched progenitors would allow for the rapid and efficient production of astrocytes that may find use in the treatment of conditions such as white matter stroke, which constitutes 30% of all stroke subtypes but currently lacks effective therapeutic approaches. White matter stroke disrupts the brain’s axonal architecture and depletes multiple cell types (including astrocytes), resulting in gait and executive function abnormalities.

In their recent Stem Cell Research article, Llorente et al. now take additional steps forward in the pre-clinical development of hiPSC-derived glial-enriched progenitors towards their application as a cell therapy for white matter stroke and neurodegenerative diseases such as multiple sclerosis, cerebral palsy, and pediatric leukodystrophies [4].

The authors described how the short-term exposure of hiPSC-NPCs with the small molecule prolyl hydroxylase inhibitor deferoxamine (which mimics the modulation of oxygen tension) generated a permanent astrocytic polarization, producing hiPSC-derived glial-enriched progenitors. The entire process required approximately one month from patient-derived hiPSCs as a starting point; in comparison, the production of astrocytes or oligodendrocyte progenitor cells from the same source can take up to six months. Importantly, hiPSC-derived glial-enriched progenitors did not exhibit signs of pluripotency, expressed elevated levels of astrocyte-specific genes (but not neuron-, oligodendrocyte-, or oligodendrocyte progenitor cell-related genes), and displayed a stable, normal karyotype. Furthermore, the authors identified a transcriptional profile characteristic of hiPSC-derived glial-enriched progenitors, comprising the expression of ADM, RAB20, PLOD2, and STC2 and a lack of STLC16A3 expression.

Viability assays next demonstrated that hiPSC-derived glial-enriched progenitors displayed a relatively high survival capacity when suspended in an appropriate media at a clinically-relevant concentration at 4 °C; notably, these assays fixed a seven-hour window from hiPSC-derived glial-enriched progenitor preparation at the bench to their clinical application with cell viability between 60-70%. Furthermore, their storage in liquid nitrogen for between two and six months failed to significantly impact their post-thaw viability. Finally, the authors assessed the safety of hiPSC-derived glial-enriched progenitor using several strategies; overall, assessments for the presence of viruses, mycoplasma, bacteria, and fungi failed to encounter any contamination, while the maximum endotoxin concentration detected was almost 100 times less than the maximum acceptable value.

Overall, these characterization and qualification steps provide robust evidence for hiPSC-derived glial-enriched progenitors as a safe and viable product ready for clinical manufacturing towards their clinical application as a therapy for white matter stroke and a range of related neurodegenerative disorders.

For more on hiPSC-derived glial-enriched progenitors and novel treatment strategies for neurodegenerative disorders, stay tuned to the Stem Cells Portal!

References

1. Xie Y, Zhang J, Lin Y, et al., Defining the Role of Oxygen Tension in Human Neural Progenitor Fate. Stem Cell Reports 2014;3:743-757.
2. Llorente Irene L, Xie Y, Mazzitelli Jose A, et al., Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents. Science Translational Medicine 2021;13:eaaz6747.
3. Xie Y and Lowry WE, Manipulation of neural progenitor fate through the oxygen-sensing pathway. Methods 2018;133:44-53.
4. Llorente IL, Hatanaka EA, Meadow ME, et al., Reliable generation of glial enriched progenitors from human fibroblast-derived iPSCs. Stem Cell Research 2021;55:102458.