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受到年龄和MI本身的损害，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脏功能的下降，否则会发生。然而，虽然这些实验通常使用年轻的健康供体小鼠，但接受自体细胞治疗的MI患者往往年龄较大并且患有MI。我们最近观察到来自老年供体小鼠的BMC缺乏这种治疗能力。此外，在几个年龄组中，我们比较了健康的供体小鼠与那些本身患有MI的小鼠，发现来自MI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BMC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，这样的解决方案是否可以直接应用于当前老年MI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，并增加了有害成分，否则有益的骨髓，而年龄减少了有益的成分。具体来说，我们将检验MI引起全身炎症反应，增加骨髓中炎症细胞的数量或激活状态的假设。高度炎症的BMC对心肌是有害的，并且可以通过在植入之前去除这些细胞来避免该问题。我们还将检验供体年龄减少骨髓中负责BMC治疗效果的有益成分的假设，与提议的由供体MI引起的有害成分增加相反。R21中产生的数据将被用作更长期研究提案的基础，旨在了解不同年龄和疾病状态如何不同地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程序中避免这些潜在问题。 公共卫生相关性：骨髓细胞输送到心脏是心脏病发作和心力衰竭的一种有前途的新治疗方法，这是密集的临床和临床前测试的主题。因为这些细胞是从患者自己的骨髓中提取的，我们将研究骨髓细胞的治疗潜力如何在老年人和心脏病患者中降低。我们还将尝试通过去除我们预测由于年龄和疾病而在骨髓中积累的特定细胞来预防这些问题。

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.