Tissue Engineering Resource Center

急性呼吸综合征窘迫综合征(ARDS)是2019年冠状病毒病最严重的并发症 (新冠肺炎)，由贝塔冠状病毒SARS-CoV-2引起。继发于新冠肺炎的急性呼吸窘迫综合征患者经常需要 机械通风支持，不幸的是死亡率超过20%(23，24，25)。间充质基质 细胞(MSC)疗法一直被考虑用于治疗广泛的炎症状况，因为它们 免疫调节能力、低免疫原性状态和出色的安全性。MSC疗法现在正在取得进展 额外关注作为抑制新冠肺炎(28)诱导的细胞因子风暴的潜在方法，如 新冠肺炎的发病与对SARS-CoV-2感染的强烈炎症反应有关，从而诱导 肺肿胀，炎细胞渗透，以及限制气体交换的非心源性肺水肿 远端肺。到目前为止，已经有20多项MSCs治疗新冠肺炎的临床试验在 临床试验.gov。同种异体骨髓间充质干细胞静脉移植在中国一小部分新冠肺炎患者中的应用 表明全身炎症明显受到抑制，临床症状明显改善。这个 作为我们P41 EB27062赠款的为期一年的补充，此处建议的研究旨在利用、扩展和结合我们的 免疫调节MSCs[19，20]和全肺生物工程[3，4，6-9，14，15]的衍生方法 建立一种治疗和预防新冠肺炎急性呼吸窘迫综合征进展的有效方法。具体来说， 我们的目标是解决三个关键问题，这三个问题将导致以简化的监管路径有效利用MSCs， 防治新冠肺炎急性呼吸窘迫综合征。问题1：骨髓间充质干细胞能否抑制之前的细胞因子风暴 缺氧和干扰素-γ？细胞预激可增强ARDS？问题2：鉴于摩根士丹利资本国际主要通过 它们产生的因子，来自预刺激的MSCs的外切体是否同样具有增强免疫调节作用的作用？ 问题3：在急性呼吸窘迫综合征的早期阶段，能否有效地利用MSC-exosome并通过雾化给药？ 直接进入肺部？为此，我们将以综合方式追求三个具体目标，通过扩大和 利用母公司赠款中开发的技术，并使用我们的高度翻译的ARDS猪模型来 建立一种新的ARDS治疗方法。

Acute respiratory syndrome distress syndrome (ARDS) is the most severe complication of coronavirus disease 2019 (COVID-19), caused by a betacoronavirus, SARS-CoV-2. Patients with ARDS secondary to COVID-19 often require mechanical ventilation support, and unfortunately present a mortality of more than 20% (23,24,25). Mesenchymal stromal cell (MSC) therapies have been under consideration for treating a wide range of inflammatory conditions due to their immunomodulatory capacity, hypoimmunogenic status, and excellent safety profile. MSC therapy is now gaining additional attention as a potential approach to suppressing the cytokine storm induced by COVID-19 (28), as the morbidity of COVID-19 is associated with strong inflammatory response to SARS-CoV-2 infection, which induces swelling of the lung, infiltration of inflammatory cells, and non-cardiogenic pulmonary edema that limits gas exchange in the distal lung. At this time, over 20 clinical trials for treating COVID-19 with MSCs have been registered with ClinicalTrials.gov. Intravenous administration of allogeneic MSCs in a small group of COVID-19 patients in China [11] indicated that the systemic inflammation was markedly suppressed and followed by improved clinical symptoms. The study proposed here as a 1-year supplement to our P41 EB27062 grant is designed to leverage, extend and combine our methodologies for derivation of immunomodulatory MSCs [19,20] and whole-lung bioengineering [3,4,6-9,14,15] towards establishing an effective modality for treating and preventing the progression of COVID-19 ARDS. Specifically, we aim to address three critical questions that would lead to the effective use of MSCs with a simplified regulatory path, to prevent and treat the COVID-19 ARDS. Question 1: Can the ability of MSCs to suppress the cytokine storm preceding ARDS be enhanced by cell priming with hypoxia and interferon-γ? Question 2: Given that the MSCs act largely by the factors they produce, would exosomes from primed MSCs simililarly have enhanced immunomodulatory effects? Question 3: Can MSC-exosomes be effectively used during the early stages of ARDS and delivered by nebulization directly into the lung? To this end, we will pursue three specific aims in an integrated fashion, by extending and leveraging the technologies developed in the parent grant, and using our highly translational swine model of ARDS to establish a novel ARDS treatment.