Omicron SARS-CoV-2 shows NRP1-linked susceptibility in adipose-derived MSCs and alters primitive cord blood CD34⁺ HSPCs.

SARS-CoV-2 infection is linked to hematologic abnormalities, but whether early hematopoietic compartments and their stromal niche are directly engaged remains unclear. We used in vitro exposure models to compare variant-associated responses of adult mesenchymal stromal cells (MSCs) and umbilical cord blood (UCB) CD34 ⁺ hematopoietic stem and progenitor cells (HSPCs). Adipose-derived (AD) and bone marrow-derived (BM) MSCs exposed to wild-type, Delta, or Omicron showed source- and variant-dependent nucleocapsid protein (NP) positivity, highest with Omicron in AD-MSCs; infectious virus in supernatants was undetectable. AD-MSCs expressed higher neuropilin-1 (NRP1) than BM-MSCs, and NRP1 knockdown reduced Omicron-associated NP signal, implicating an NRP1-linked entry process. SARS-CoV-2 exposure induced indoleamine-2,3-dioxygenase 1 (IDO1), most prominently in AD-MSCs. In UCB CD34 ⁺ HSPCs, Omicron increased NP positivity enriched in long-term HSCs, reduced primitive fraction frequencies, increased colony formation, and promoted early erythroid progenitor accumulation; heat-inactivated virus did not. NanoString profiling revealed host-response activation and altered cell-cycle/differentiation programs. These data indicate Omicron can engage stromal and early hematopoietic compartments and remodel stress-responsive hematopoiesis.