Tetraspanin CD82 Regulates Hematopoietic Stem and Progenitor Cell Quiescence and Stress

The hematopoietic system relies on a rare pool of hematopoietic stem cells (HSCs), typically maintained in quiescence but capable of activation, self-renewal, and differentiation under stress. While HSC activation is essential, mechanisms controlling quiescence and activation are not fully understood. Tetraspanins, such as CD82, are membrane scaffold proteins that regulate signaling via tetraspanin-enriched microdomains. CD82 has been identified as a critical modulator of HSC quiescence, with CD82 knockout (KO) mice showing increased HSC activation. We demonstrate that CD82 enhances TGF-β signaling by facilitating receptor crosstalk between TGF-β receptor I and integrin β1, modulating cell proliferation. Under stress, CD82 expression is significantly upregulated, promoting cell survival. CD82 knockdown increases cell death, underscoring its protective role against apoptosis. Collectively, our findings indicate that CD82 is crucial for regulating HSC quiescence, TGF-β signaling, and stress resilience, positioning it as a potential therapeutic target to enhance HSC function and survival in transplantation contexts.