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Human iPSC-derived mesenchymal stem cells relieve high blood pressure in spontaneously hypertensive rats via splenic nerve activated choline acetyltransferase-positive cells

Zhang Zhen,Huang Weijun,Zhang Xiaoran,Wang Zhecun,Xie Manting,Xie Bingbing,Wang Yiling,Chen Xiaoyong,Xiang Andy Peng,Xiang Qiuling

Despite substantial advancements in modern medicine, the management of hypertension remains a major challenge. Stem cell-based therapies have recently demonstrated remarkable efficacy in treating cardiovascular diseases, including hypertension. However, the antihypertensive mechanism of mesenchymal stem cells (MSCs) has not been extensively explored. This study aimed to investigate the role of injected MSCs in regulating blood pressure homeostasis. Our previous study demonstrated that human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) are functional and homogeneous sources for MSC-based therapy. After the injection of hiPSC-MSCs, a significant reduction in blood pressure and end target organ inflammation were observed in spontaneously hypertensive rats (SHRs). Cell tracking assays demonstrated that the injected hiPSC-MSCs accumulated in the spleens of the SHRs. The injected hiPSC-MSCs accumulated adjacent to the splenic nerve, potentially contributing to the antihypertensive effects. Furthermore, the hiPSC-MSCs released abundant glutamate, which acts as a neuromodulator to activate the splenic sympathetic nerve. After inhibition of glutamate synthesis by siRNA, the ability of hiPSC-MSCs to activate sympathetic nerves was significantly diminished. In addition, the antihypertensive effects of hiPSC-MSCs were eliminated after splenic nerve denervation (SND), underscoring the critical role of the splenic nerve. Moreover, activation of the splenic nerve resulted in increased release of norepinephrine (NE), which increased the number of choline acetyltransferase-positive (ChAT + ) cells in the spleen and peripheral blood. Consequently, the acetylcholine (ACh) produced by elevated ChAT + cells could act as a vasodilator, lowering blood pressure and mitigating inflammation in end target organs. In summary, our findings indicate that hiPSC-MSCs effectively lower blood pressure in hypertension by influencing the splenic nerves and regulating ChAT + cells. The connection between blood pressure regulation and the splenic nerve may offer new insights into the treatment of hypertension.