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)的自体细胞疗法如何受到年龄和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，将小鼠骨髓细胞(BMC)移植到心肌梗死(MI)后的小鼠心脏可以防止原本会发生的心功能下降。然而，虽然这类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心肌梗死患者往往年龄较大，并患有心肌梗死。我们最近观察到，来自老年供体小鼠的骨髓细胞缺乏这种治疗能力。此外，在几个年龄组中，我们比较了健康的供体小鼠和那些自己有心肌梗死的小鼠，发现患有心肌梗死的供体的骨髓细胞在治疗上也受到了损害。我们将回答以下问题：是什么导致这种与年龄和脑梗塞相关的骨髓细胞损害？捐献者年龄和疾病的负面影响是否通过不同的机制发挥作用？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骨髓细胞治疗？我们的一般假设是，心肌梗塞增加了骨髓的炎症状态，并在原本有益的骨髓中增加了有害成分，而年龄则减少了有益成分。具体地说，我们将检验这一假设，即心肌梗死引起全身炎症反应，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有害，通过在植入前移除这些细胞可以绕过这个问题。我们还将检验这一假设，即供者年龄减少了骨髓中负责骨髓细胞治疗效果的有益成分，而不是供者心肌梗死导致有害成分的拟议增加。R21中产生的数据将被用作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不同地影响骨髓细胞的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治疗心脏病发作和心力衰竭的一种很有前途的新疗法，这是密集的临床和临床前试验的主题。由于这些细胞是从患者自己的骨髓中提取的，我们将研究如何降低老年人和心脏病患者的骨髓细胞治疗潜力。我们还将试图通过移除我们预测的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.