Pericytes within Assembloid Model Supports Study of SARS‑CoV‑2 Infection

Review of "A human three-dimensional neural-perivascular 'assembloid' promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology" from Nature Medicine by Stuart P. Atkinson

Reports have linked the onset of central nervous system pathologies with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infections [1], and recent evidence proposes neurovascular components, and neural crest stem cell-derived brain pericytes in particular [2-5], as viral entry points using angiotensin-converting enzyme 2 (ACE2) as a receptor. In a recent study published in Nature Medicine, researchers led by Joseph G. Gleeson and Aaron F. Carlin (University of California San Diego, La Jolla, CA, USA) reported that pericyte-like cell-containing cortical organoids (an "assembloid" model) supported SARS-CoV-2 entry and replication in neural tissue and may therefore represent an exciting new platform for related studies [6].

Wang et al. discovered that the integration of ACE2-expressing pericyte-like cells (generated in vitro from human pluripotent stem cell-derived neural crest stem cells) into cortical brain organoids at the corticogenesis stage (60–74 days of in vitro culture) promoted astrocytic maturation, increased basement membrane component production, and supported ongoing neurogenesis in the absence of viral infection, Importantly, these features are typically attributed to human brain pericytes in vivo. Interestingly, cortical organoids lacking pericyte-like cells displayed few signs of active infection by SARS-CoV-2; however, the pericyte-like cell-containing cortical organoids played the role of viral replication hubs with the produced virus spreading to nearby astrocytes. Of note, increased cell death and the induction of inflammatory type I interferon transcriptional responses accompanied the spread through the assembloid model.

Overall, this assembloid model provides evidence for an alternative SARS-CoV-2 infection route; however, the authors note that incorporating other neurovascular unit component cell types may improve their assembloid model further and extend its use to the study of related diseases and disorders [7].

For more on the exciting future of pericyte-like cell-containing assembloid models, stay tuned to the Stem Cells Portal!

References

1. Solomon T, Neurological infection with SARS-CoV-2 — the story so far. Nature Reviews Neurology 2021;17:65-66.
2. He L, Mäe MA, Muhl L, et al., Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19. bioRxiv 2020:2020.05.11.088500.
3. Zlokovic BV, Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nature Reviews Neuroscience 2011;12:723-738.
4. Brann DH, Tsukahara T, Weinreb C, et al., Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv 2020;6.
5. Khaddaj-Mallat R, Aldib N, Paquette A-S, et al., SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection. bioRxiv 2021:2021.04.30.442194.
6. Wang L, Sievert D, Clark AE, et al., A human three-dimensional neural-perivascular 'assembloid' promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology. Nature Medicine 2021.
7. Hall CN, Reynell C, Gesslein B, et al., Capillary pericytes regulate cerebral blood flow in health and disease. Nature 2014;508:55-60.