Bone marrow cell therapy for cardiac disease: Impact of donor age and infarction

描述（由申请人提供）：拟议的研究将确定心肌梗死（MI）的自体细胞治疗如何因年龄和MI本身而受损，以及如何避免这种损害。我们和其他人已经证明，在心肌梗死（MI）后，将小鼠骨髓细胞（bmc）植入小鼠心脏可以防止心功能的下降。然而，虽然此类实验通常使用年轻健康的供体小鼠，但接受自体细胞治疗的心肌梗死患者往往年龄较大且患有心肌梗死。我们最近观察到，来自老年供体小鼠的骨髓基质缺乏这种治疗能力。此外，在几个年龄组中，我们将健康的供体小鼠与本身患有心肌梗死的供体小鼠进行了比较，发现来自心肌梗死供体的bmc也在治疗上受损。我们将回答以下问题：是什么原因导致这种年龄和梗死相关的脑血管损伤？供体年龄和疾病的负面影响是否通过不同的机制起作用？在我们的实验模型中如何防止这些负面影响？最重要的是，这种解决方案能否直接应用于目前老年心肌梗死后患者群体的临床自体BMC治疗？我们的一般假设是心肌梗死增加了骨髓的炎症状态，为原本有益的骨髓增加了有害成分，而年龄则减少了有益成分。具体来说，我们将验证心肌梗死引起全身炎症反应的假设，从而增加骨髓中炎症细胞的数量或激活状态。高度炎症的骨髓细胞对心肌是有害的，通过在植入前移除这些细胞可以避免这个问题。我们还将检验供体年龄降低骨髓中负责BMCs治疗效果的有益成分的假设，与供体心肌梗死引起的有害成分的增加形成对比。本R21中产生的数据将作为更长期研究建议的基础，旨在了解不同年龄和疾病状态如何差异影响骨髓细胞治疗能力的机制细节。以及如何在临床细胞治疗过程中避免这些潜在的问题。

DESCRIPTION (provided by applicant): The proposed research will determine how autologous cell therapy for myocardial infarction (MI) can be impaired by age and the MI itself, and how this impairment can be avoided. We and others have demonstrated that implantation of mouse bone marrow cells (BMCs) into mouse hearts after myocardial infarction (MI) can prevent the decline in cardiac function that would otherwise occur. However, while such experiments typically use young healthy donor mice, MI patients undergoing autologous cell therapy tend to be older and have had an MI. We have recently observed that BMCs from old donor mice lack this therapeutic capacity. Furthermore, in several age groups, we have compared healthy donor mice with those that have themselves had an MI, and find that BMCs from donors with MI are also therapeutically impaired. We will answer the following questions: What causes this age- and infarct-related impairment of the BMCs? Do the negative effects of donor age and disease work through different mechanisms? How can these negative effects be prevented in our experimental model? Most importantly, can such a solution be directly applied to current clinical autologous BMC therapy of the aged, post-MI patient population? Our general hypothesis is that MI increases the inflammatory state of the bone marrow and adds a deleterious component to the otherwise-beneficial bone marrow, whereas age decreases the beneficial component. Specifically, we will test the hypothesis that MI causes a systemic inflammatory response that increases the number or activation state of inflammatory cells in the bone marrow. The hyper-inflammatory BMCs are deleterious to the myocardium, and the problem can be circumvented by removing these cells prior to implantation. We will also test the hypothesis that donor age reduces the beneficial component of the bone marrow responsible for the BMCs' therapeutic effect, in contrast with the proposed increase in the deleterious component caused by donor MI. The data generated in this R21 will be used as the basis of more long-term research proposals, aimed at understanding the mechanistic details of how different age and disease states differentially affect the therapeutic capacity of cells in the bone marrow, and how these potential problems can be avoided in clinical cell therapy procedures. PUBLIC HEALTH RELEVANCE: Bone marrow cell delivery to the heart is a promising new treatment for heart attacks and heart failure that is the subject of intense clinical and preclinical testing. Because these cells are taken from the patient's own bone marrow, we will study how the therapeutic potential of bone marrow cells can be decreased in older individuals and those with heart disease. We will also attempt to prevent these problems by removing specific cells that we predict have accumulated in the bone marrow as a result of the age and disease.