Dppa5 Improves Hematopoietic Stem Cell Activity by Reducing Endoplasmic Reticulum Stress

• Dppa5 overexpression improves function of hematopoietic stem cells (HSCs)
• Downregulation of Dppa5 profoundly impairs long-term reconstitution of HSCs
• Dppa5 reduces endoplasmic reticulum (ER) stress in HSCs
• Reduction of ER stress by a chemical chaperone improves HSC function

SummaryDevelopmental pluripotency-associated 5 (Dppa5) is an RNA binding protein highly expressed in undifferentiated pluripotent stem cells. Here, we demonstrate that Dppa5 is a regulator of hematopoietic stem cells (HSCs) that critically governs reconstitution capacity after bone marrow transplantation. Ectopic expression of Dppa5 followed by in vitro culture robustly increased HSC reconstitution levels through suppression of endoplasmic reticulum (ER) stress and apoptosis. Remarkably, a chemical chaperone that decreases ER stress in HSCs also increases HSC engraftment. Conversely, knockdown of Dppa5 impaired the long-term reconstitution ability of HSCs due to elevated ER stress levels, suggesting that ER stress regulation is physiologically important for proper HSC function in vivo. Thus, Dppa5 represents a pivotal connection between ER stress regulation and stem cell properties in HSCs. The findings also demonstrate that protein quality control is critical for the maintenance, survival, and function of HSCs in vivo and ex vivo.

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