Ringdén Olle, Moll Guido, Gustafsson Britt, Sadeghi Behnam
Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden.
Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
Front Immunol. 2022 Mar 18;13:839844. doi: 10.3389/fimmu.2022.839844. eCollection 2022.
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
间充质基质细胞（MSCs）具有强大的免疫调节和再生特性，在众多存在未满足医疗需求的临床适应症中具有临床应用价值。MSCs的常见来源包括骨髓（BM）、脂肪、脐带和胎盘来源的蜕膜基质细胞（DSCs）。在此，我们总结了20多年来在不同临床环境中使用MSCs和DSCs的科学经验。大约30年前，人们首次探索了BM-MSCs以提高自体移植物在造血细胞移植（HCT）和成骨不全中的植入率。2004年，我们团队报道了BM-MSCs在一名IV级急性移植物抗宿主病（GvHD）患儿中的首次抗炎应用。随后的研究表明，MSCs在急性GvHD中似乎比慢性GvHD更有效。如今，BM-MSC疗法在日本已注册用于治疗急性GvHD，在加拿大和新西兰已注册用于治疗儿童GvHD。静脉注射后，MSCs首先归巢至肺，并对宿主免疫系统发挥强大的局部和全身免疫调节作用。因此，人们研究了它们用于改善急性呼吸窘迫综合征（ARDS）中的细胞因子风暴。MSCs和DSCs都被用于治疗严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）相关的ARDS。此外，它们还被用于其他新的适应症，如纵隔气肿、结肠穿孔和神经根脊髓病。MSCs和DSCs会触发凝血，因此被探索用于止血。DSCs在急性GvHD、ARDS和出血方面似乎更有效，但需要随机研究来证明其优越性。基质细胞输注是安全的，耐受性良好，仅在少数患者中引起轻微发热，但多项安全性研究和荟萃分析均未报告重大副作用。在本综述中，我们总结了来自研究、动物模型以及重要的是我们临床经验的当前证据，以支持基质细胞疗法在多种临床适应症中的应用。这包括MSCs对免疫系统、凝血的影响及其安全性和有效性，并结合该领域的重要临床试验进行讨论。
