Pot1a maintains mesenchymal stem cell niche function to support hematopoietic stem cells

Hematopoietic stem cells (HSCs) maintain their function through interactions with niche cells in the bone marrow. We previously demonstrated that protection of telomeres 1a (Pot1a), a shelterin component, maintains HSCs and neuron-glial antigen 2-expressing (NG2⁺) mesenchymal stem cells (MSCs) by suppressing DNA damage response (DDR) and reactive oxygen species (ROS) production. However, the role of Pot1a in leptin receptor-expressing (LepR⁺) MSCs, a primary HSC niche component, remains unclear. LepR-specific Pot1a knockout mice showed decreased LepR⁺ MSC numbers, increased DDR and ROS production, reduced HSC quiescence, and impaired long-term hematopoietic reconstitution. In contrast, cell-permeable Pot1a enhanced the hematopoietic-supporting function of LepR⁺ MSCs. Pot1a deficiency reduced pleiotrophin (Ptn) expression, whereas Pot1a overexpression increased its expression. These findings suggest that Pot1a preserves LepR⁺ MSC function by limiting stress-associated changes, maintaining MSC numbers, and regulating hematopoietic-supportive factor expression, including PTN.