Division of Nephrology and Hypertension, Mayo Clinic, 200, First Street SW, Rochester, 55902, MN, USA.
Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu province, China.
Stem Cell Res Ther. 2024 Jun 9;15(1):162. doi: 10.1186/s13287-024-03778-1.
Autologous mesenchymal stem cells (MSCs) have emerged as a therapeutic option for many diseases. Hypertensive kidney disease (HKD) might impair MSCs' reparative ability by altering the biomolecular properties, but the characteristics of this impairment are unclear. In our previous pre-clinical studies, we found hypoxic preconditioning (HPC) enhanced angiogenesis and suppressed senescence gene expression. Thus, we hypothesize that HPC would improve human MSCs by enhancing their functionality and angiogenesis, creating an anti-inflammatory and anti-senescence environment.
MSC samples (n = 12 each) were collected from the abdominal fat of healthy kidney donors (HC), hypertensive patients (HTN), and patients with hypertensive kidney disease (HKD). MSCs were harvested and cultured in Normoxic (20% O) or Hypoxic (1% O) conditions. MSC functionality was measured by proliferation assays and cytokine released in conditioned media. Senescence was evaluated by senescence-associated beta-galactosidase (SA-beta-gal) activity. Additionally, transcriptome analysis using RNA-sequencing and quantitative PCR (qPCR) were performed.
At baseline, normoxic HTN-MSCs had higher proliferation capacity compared to HC. However, HPC augmented proliferation in HC. HPC did not affect the release of pro-angiogenic protein VEGF, but increased EGF in HC-MSC, and decreased HGF in HC and HKD MSCs. Under HPC, SA-β-gal activity tended to decrease, particularly in HC group. HPC upregulated mostly the pro-angiogenic and inflammatory genes in HC and HKD and a few senescence genes in HKD.
HPC has a more favorable functional effect on HC- than on HKD-MSC, reflected in increased proliferation and EGF release, and modest decrease in senescence, whereas it has little effect on HTN or HKD MSCs.
自体间充质干细胞（MSCs）已成为许多疾病的治疗选择。高血压肾病（HKD）可能通过改变生物分子特性来损害 MSCs 的修复能力，但这种损害的特征尚不清楚。在我们之前的临床前研究中，我们发现低氧预处理（HPC）增强了血管生成并抑制了衰老基因的表达。因此，我们假设 HPC 通过增强其功能和血管生成来改善人 MSCs，从而创造一个抗炎和抗衰老的环境。
从健康肾脏供体（HC）、高血压患者（HTN）和高血压肾病患者（HKD）的腹部脂肪中采集 MSC 样本（每组各 12 个）。MSC 被收获并在常氧（20% O）或低氧（1% O）条件下培养。通过增殖试验和条件培养基中细胞因子的释放来测量 MSC 的功能。通过衰老相关的β-半乳糖苷酶（SA-β-gal）活性来评估衰老。此外，还进行了 RNA 测序和定量 PCR（qPCR）的转录组分析。
在基线时，常氧 HTN-MSC 的增殖能力高于 HC。然而，HPC 增强了 HC 的增殖。HPC 不影响促血管生成蛋白 VEGF 的释放，但增加了 HC-MSC 中的 EGF，并减少了 HC 和 HKD MSC 中的 HGF。在 HPC 下，SA-β-gal 活性趋于下降，特别是在 HC 组。HPC 上调了 HC 和 HKD 中大多数促血管生成和炎症基因，以及 HKD 中少数衰老基因。
HPC 对 HC-MSC 的功能影响比对 HKD-MSC 更有利，表现在增殖和 EGF 释放增加，衰老适度减少，而对 HTN 或 HKD MSC 影响较小。
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