当前位置: X-MOL 学术Stem Cells Transl. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
In reply.
STEM CELLS Translational Medicine ( IF 6 ) Pub Date : 2020-04-22 , DOI: 10.1002/sctm.20-0112
Anna Krasnodembskaya 1
Affiliation  

We appreciate the interest in our recent publication1 from Ji and colleagues2 and thank them for their letter. The authors report on initiating a clinical trial (NCT04252118) to use umbilical cord‐derived mesenchymal stem cells (UC MSC) as cell therapy to treat COVID‐19 infected patients who have developed pneumonia. One of the mechanisms by which coronaviruses cause extensive lung damage and mortality is due to the induction of unregulated inflammatory response leading to development of acute respiratory distress syndrome (ARDS). In view of the recent WHO declaration of COVID‐19 as a pandemic, there is an urgent need to find methods to alleviate the severity of COVID‐19‐induced acute lung injury, which represents the major cause of mortality in infected patients.

MSCs‐based therapy is being considered as a promising approach for ARDS because of robust preclinical evidence of MSC's ability to target major aspects of ARDS pathophysiology.3, 4 Furthermore, data from early phase clinical trials suggest that it is safe to give MSCs to patients with ARDS.5, 6 In addition, the MUST‐ARDS study conducted by Athersys Inc with a patented bone marrow‐derived adult multipotent progenitor cell product “MultiStem” reported a significant reduction in 28‐day mortality accompanied by an increase in both ventilator‐ and intensive care unit‐free days in patients who had received cell therapy.7 Ji and colleagues also refer to the UC MSC effectiveness in the NCT03608592 trial; however, no published data on the results of this trial have been made available yet, and according to ClinicalTrials.gov, this trial has a recruitment phase status with estimated completion date of 1 December 2020.

Unfortunately, preclinical data on the effects of MSCs in viral‐induced lung injury are limited. That is predominantly due to the fact that it is very difficult to model human viral infections in animals. The available data suggest that effects of MSCs appear to depend on the specific viral strain. MSCs significantly attenuated H9N2 avian influenza, as well as H5N1 virus‐induced acute lung injury and inflammation, in mice.8, 9 In contrast, MSCs failed to protect mice from lung injury caused by influenza A pneumonia (a mouse‐adapted H1N1, PR8).10, 11 To the best our knowledge, there are no data on MSC effectiveness in coronavirus‐induced lung injury. This further reiterates the need for establishment and wider adoption of in vivo animal models with natural human target cells to accelerate the development and testing of effective therapeutics for many highly relevant human pathogens. One such model, based on subcutaneous implantation of human lung tissue into humanized mice, was recently reported by Wahl et al.12

Another important aspect to consider is that MSCs themselves might be susceptible to viral infections, and such infection may alter their immunomodulatory and reparative properties.13, 14 In this regard, MSC cell products and specifically MSC‐derived extracellular vesicles (EVs) could represent a better alternative to the MSC whole cell therapy. In fact, a recent publication by Loy et al suggests that MSC‐EVs were effective in attenuating influenza A(H5N1)‐induced acute lung injury in pigs.15

In conclusion, the safety of MSC administration has been confirmed in numerous clinical trials, so it is unlikely that their administration would cause unwanted adverse effects in the COVID‐19 patients' cohort. At the same time, well‐established immunomodulatory and reparative capacities of MSCs (although not directly tested in preclinical models for this particular application) make them promising candidates to test in this urgent scenario. Further effective development of MSC‐based therapy will be important to investigate the mechanisms of their therapeutic effects in the context of viral pneumonia using clinical samples from patients enrolled in this trial.

We wish the authors success in their study and, most importantly, full recovery to all COVID‐19 infected patients.



中文翻译:

回复。

感谢Ji和同事2对我们最近的出版物1的关注,并感谢他们的来信。作者报告启动一项临床试验(NCT04252118),以使用脐带来源的间充质干细胞(UC MSC)作为细胞疗法来治疗感染COVID-19的肺炎患者。冠状病毒引起广泛的肺损伤和死亡的机制之一是由于诱导了不受调节的炎症反应,从而导致了急性呼吸窘迫综合征(ARDS)的发展。鉴于世界卫生组织最近宣布COVID-19为大流行,迫切需要找到减轻COVID-19引起的急性肺损伤的严重程度的方法,这是感染患者死亡的主要原因。

基于MSCs的治疗被认为是ARDS的一种有前途的方法,因为有充分的临床前证据证明MSC具有针对ARDS病理生理学主要方面的能力。[3,4]此外,来自早期临床试验的数据表明,将MSCs用于ARDS患者是安全的。5,6此外,由Athersys Inc.对获得专利的骨髓成年多能祖细胞产品“ MultiStem”进行的MUST-ARDS研究报告,其28天死亡率显着降低,同时呼吸机和重症监护均增加接受细胞治疗的患者的无单位天数。7Ji及其同事在NCT03608592试验中还提到了UC MSC的有效性。但是,尚未提供有关该试验结果的公开数据,并且根据ClinicalTrials.gov的说法,该试验处于募集阶段,预计完成日期为2020年12月1日。

不幸的是,有关MSC在病毒性肺损伤中作用的临床前数据有限。这主要是由于很难在动物中模拟人类病毒感染这一事实。现有数据表明,MSC的作用似乎取决于特定的病毒株。MSC可显着减轻H9N2禽流感以及H5N1病毒诱发的小鼠急性肺损伤和炎症。8,9相比之下,MSC无法保护小鼠免受甲型流感病毒(适应小鼠的H1N1,PR8)引起的肺损伤。10、11据我们所知,尚无关于在冠状病毒引起的肺损伤中MSC有效性的数据。这进一步重申需要建立和广泛采用具有天然人靶细胞的体内动物模型,以加速开发和测试许多高度相关的人类病原体的有效疗法。Wahl等人最近报道了一种基于将人肺组织皮下植入人源化小鼠的模型。12

要考虑的另一个重要方面是,MSC本身可能易受病毒感染,并且这种感染可能会改变其免疫调节和修复特性。[13,14]在这方面,MSC细胞产物,特别是MSC衍生的细胞外囊泡(EV)可以代表MSC全细胞疗法的更好替代方案。实际上,Loy等人的最新出版物表明,MSC-EV可有效减轻猪中由A(H5N1)流感引起的急性肺损伤。15

总之,在许多临床试验中已经证实了MSC给药的安全性,因此它们的给药不太可能在COVID-19患者队列中引起不良副作用。同时,成熟的MSCs的免疫调节和修复能力(尽管未在针对该特定应用的临床前模型中直接测试)使它们有望在紧急情况下进行测试。基于MSC的疗法的进一步有效开发对于使用来自该试验的患者的临床样本研究病毒性肺炎的治疗作用机制至关重要。

我们希望作者在研究中取得成功,最重要的是,祝愿所有COVID-19感染患者都能完全康复。

更新日期:2020-06-23
down
wechat
bug