Human Hematopoietic Stem, Progenitor, and Immune Cells Respond Ex Vivo to SARS-CoV-2 Spike Protein

Abstract

Despite evidence that SARS-CoV-2 infection is systemic in nature, there is little known about the effects that SARS-CoV-2 infection or exposure has on many host cell types, including primitive and mature hematopoietic cells. The hematopoietic system is responsible for giving rise to the very immune cells that defend against viral infection and is a source of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) which are used for hematopoietic cell transplantation (HCT) to treat hematologic disorders, thus there is a strong need to understand how exposure to the virus may affect hematopoietic cell functions. We examined the expression of ACE2, to which SARS-CoV-2 Spike (S) protein binds to facilitate viral entry, in cord blood derived HSCs/HPCs and in peripheral blood derived immune cell subtypes. ACE2 is expressed in low numbers of immune cells, higher numbers of HPCs, and up to 65% of rigorously defined HSCs. We also examined effects of exposing HSCs/HPCs and immune cells to SARS-CoV-2 S protein ex vivo. HSCs and HPCs expand less effectively and have less functional colony forming capacity when grown with S protein, while peripheral blood monocytes upregulate CD14 expression and show distinct changes in size and granularity. That these effects are induced by recombinant S protein alone and not the infectious viral particle suggests that simple exposure to SARS-CoV-2 may impact HSCs/HPCs and immune cells via S protein interactions with the cells, regardless of whether they can be infected. These data have implications for immune response to SARS-CoV-2 and for HCT. Graphical Abstract • Human HSCs, HPCs, and immune cells express ACE2 on the cell surface, making them potentially susceptible to SARS-CoV-2 infection. • SARS-CoV-2 S protein, which binds to ACE2, induces defects in the colony forming capacity of human HPC and inhibits the expansion of HSC/HPC subpopulations ex vivo . These effects can be at least partially neutralized by treatment with SARS-CoV-2 targeting antibody, recombinant human ACE2, or Angiotensin1–7. • S protein also induces aberrant morphological changes in peripheral blood derived monocytes ex vivo . • Thus, there are many different manners in which SARS-CoV-2 virus may impact the functional hematopoietic system, which has important implications for hematological manifestations of COVID-19 (i.e. thrombocytopenia and lymphopenia), immune response, and hematopoietic stem cell transplant in the era of COVID-19. Electronic supplementary material The online version of this article (10.1007/s12015-020-10056-z) contains supplementary material, which is available to authorized users.

COVID-19 as a systemic disease

“…Экспрессия вирусных рецепторов (АПФ2) оказывается достаточно сильной в родоначальных клетках крови, она слабее в клеткахпредшественницах и представлена в небольшом пуле периферических моноцитов. Взаимодействие S-протеина с названными клетками хотя и не приводит к проникновению вирусов в них, тем не менее, в клетках-родоначальницах/предшественницах вирус вызывает подавление колониеобразующей способности, а в периферических моноцитах запускает их трансформацию в макрофаги [124].…”

Endothelial progenitor cells in pathogenesis of new coronaviral infection

“…Впервые показано [26], что AПФ2 и трансмембранная протеиназа TMPRSS2, способствующая проникновению вируса, экспрессируются на очень маленьких эмбрионоподобных стволовых клетках CD133+CD34+Lin-CD45-, депонированных во взрослых тканях человека, которые могут трансформироваться в функциональные гемопоэтические стволовые клетки и ЭПК. Авторы впервые показали, что в этих клетках человека взаимодействие рецептора AПФ2 с белкомшипом SARS-CoV-2 активирует многобелковый комплекс инфламмасомы Nlrp 3 , что может привести к гибели клеток вследствие пироптоза (рис.…”

Stem Cells as Potential Therapeutics and Targets for Infection by COVID19 – Special Issue on COVID19 in Stem Cell Reviews and Reports

“…In an elegant review, Dr. Smadja addressed hematological complications of COVID19 infection [ 2 ]. Moreover, in this special issue, there are published two experimental papers demonstrating the consequences of the presence of COVID19 entry receptor ACE2 on hematopoietic stem progenitor cells (HSPCs) [ 3 , 4 ]. What is important is that expression of this receptor, as demonstrated, increases with more primitive phenotype of stem/progenitor cells [ 3 ].…”

“…Moreover, in this special issue, there are published two experimental papers demonstrating the consequences of the presence of COVID19 entry receptor ACE2 on hematopoietic stem progenitor cells (HSPCs) [ 3 , 4 ]. What is important is that expression of this receptor, as demonstrated, increases with more primitive phenotype of stem/progenitor cells [ 3 ]. It is why it is not surprising why ACE2 is highly expressed on very small embryonic-like stem cells that, as reported by several laboratories, may correspond to very primitive stem cell population residing in adult tissues [ 5 ].…”

“…What is also very important, Dr. Broxmeyer’s group demonstrated that exposure of HSPCs to recombinant COVID19 spike protein results in a decrease of clonogenicity of progenitor cells in all major hematopoietic lineages [ 3 ]. The specificity of this effect on clonogeneic growth of HSPCs has been demonstrated by preincubation of spike protein with human recombinant ACE2 protein or anti-ACE2 blocking antibodies [ 3 ]. In addition, Dr. Kucia et al provided evidence that spike protein interaction with HSPCs as well as with endothelial progenitor cells hyperactivates Nlrp3 inflammasome [ 4 ].…”