Bone Marrow SSEA1+ Cells Support the Myocardium in Cardiac Pressure Overload

RationaleStage specific embryonic antigen 1+ (SSEA1+) cells have been described as the most primitive mesenchymal progenitor cell in the bone marrow. Cardiac injury mobilizes SSEA1+ cells into the peripheral blood but their in vivo function has not been characterized. ObjectiveWe generated animals with chimeric bone marrow to determine the fate and function of bone marrow SSEA1+ cells in response to acute cardiac pressure overload. Methods and ResultsLethally irradiated mice were transplanted with normal bone marrow where the wild-type SSEA1+ cells were replaced with green fluorescent protein (GFP) SSEA1+ cells. Cardiac injury was induced by trans-aortic constriction (TAC). We identified significant GFP+ cell engraftment into the myocardium after TAC. Bone marrow GFP+ SSEA1 derived cells acquired markers of endothelial lineage, but did not express markers of c-kit+ cardiac progenitor cells. The function of bone marrow SSEA1+ cells after TAC was determined by transplanting lethally irradiated mice with bone marrow depleted of SSEA1+ cells (SSEA1-BM). The cardiac function of SSEA1-BM mice declined at a greater rate after TAC compared to their complete bone marrow transplant counterparts and was associated with decreased bone marrow cell engraftment and greater vessel rarefication in the myocardium. ConclusionsThese results provide evidence for the recruitment of endogenous bone marrow SSEA1+ cells to the myocardium after TAC. We demonstrate that, in vivo, bone marrow SSEA1+ cells have the differentiation potential to acquire endothelial lineage markers. We also show that bone marrow SSEA1+ deficiency is associated with a reduced compensatory capacity to cardiac pressure overload, suggesting their importance in cardiac homeostasis. These data demonstrate that bone marrow SSEA1+ cells are critical for sustaining vascular density and cardiac repair to pressure overload.

研究背景：阶段特异性胚胎抗原1阳性（SSEA1+）细胞曾被认为是骨髓中最原始的间充质祖细胞。心脏损伤可将SSEA1+细胞动员至外周血，但该细胞在体内的功能尚未被阐明。研究目的：本研究通过构建骨髓嵌合小鼠模型，探究骨髓SSEA1+细胞在急性心脏压力负荷应激下的命运与功能。方法与结果：本研究将野生型SSEA1+细胞替换为绿色荧光蛋白（GFP）标记的SSEA1+细胞的正常骨髓，移植至经致死剂量照射的小鼠体内。通过主动脉弓缩窄术（TAC）构建心脏损伤模型。结果显示，TAC术后可见大量GFP+细胞定植于心肌组织。骨髓来源的GFP+ SSEA1+细胞可获得内皮细胞谱系标志物，但不表达c-kit阳性心脏祖细胞的标志物。为明确骨髓SSEA1+细胞在TAC术后的功能，本研究将经致死剂量照射的小鼠移植去除SSEA1+细胞的骨髓（SSEA1-BM）。与接受完整骨髓移植的对照组小鼠相比，SSEA1-BM小鼠在TAC术后心功能下降速率更快，且伴随骨髓细胞定植减少、心肌血管稀疏程度加重。结论：本研究结果证实，TAC术后内源性骨髓源性SSEA1+细胞可被招募至心肌组织。本研究证明，骨髓SSEA1+细胞在体内具有分化为内皮细胞谱系的潜能。同时发现，骨髓SSEA1+细胞缺失会降低心脏对压力负荷的代偿能力，提示该细胞在心脏稳态维持中发挥重要作用。上述数据表明，骨髓SSEA1+细胞对于维持血管密度及心脏对抗压力负荷的修复过程至关重要。