GCSF Treatment for Non-Ischemic Dilated Cardiomyopathy

Abstract

In 2001 research of endogenous cell therapy started. Orlic et al. reported that granulocyte colony-stimulating factor (GCSF) and stem-cell-factor (SCF) improved heart function and the survival rate after myocardial infarction [1]. They showed that the infarcted scar got smaller with newly-formed myocardium dramatically. Because they did not label bone marrow cells, it was not sure where the majority was originated from. To clarify this issue we tagged bone marrow cells with GFP for tracking [2]. Survival rate was improved with GCSF. However, Bone marrow-derived myogenic cells were too small number to contribute to pump function directly [3]. This observation made researchers to go to other directions. Wei et al. clearly showed that in doxorubicininduced cardiomyopathy the protein expression of Fas was attenuated by GCSF and apoptosis of cardiomyocytes was inhibited and ultrastructure of myocardium was well preserved. Finally GCSF improved heart function, which was confirmed by pressure study and echocardiography. This mechanism of GCSF treatment was consistent with infarction model [4]. GCSF receptors are expressed on cardiomyocytes in idiopathic dilated cardiomyopathy in human, too [5]. GCSF affected not only bone marrow to mobilize cells to migrate into diseased heart but also cardiomyocytes directly through GCSF receptors. In the time course rats received GCSF from 2 weeks after doxorubicin induction. At the period of GCSF treatment myocardium is still in the subacute phase after doxorubicin. We observed that GCSF effectiveness was vague 3 weeks after doxorubicin induction [6]. It is likely to have much more effectiveness just after insult such as infarction [4], cardiotoxic drug, and so on. However, in the clinical setting, end-staged dilated cardiomyopathy is the reality. GCSF strategy should be investigated in the chronic phase in the further study. GCSF regimen such as dose, frequency, and duration should be optimized, too. As a preclinical study nonischemic cardiomyopathy in large animal models should be investigated. There are other possible mechanisms of GCSF. First, the healing process. Minatoguchi et al. reported that GCSF accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs [7]. Second, cardiac resident stem cells. Oh et al. reported that Sca 1(+ ) cells reside at the central fibrous body and atrium and they can be expanded in vitro and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells [8]. Cardiac resident stem cells may play an important role in the GCSF treatment. Third, other roles of bone marrowderived cells. Interpretations of mobilized bone marrow cells by Skalak’s lab is interesting [9]. They reported that mobilization of bone marrow-derived cells enhanced the angiogenic response to hypoxia without transdifferentiation into endothelial cells. Adult stem cells may work as supervisors, not doing the heavy lifting themselves. It will take some time to clarify what is the major mechanism to improve damaged heart function with GCSF treatment. Sata et al. reported that hematopoietic stem cells may contribute to atherosclerosis [10]. It raised the important point that endogenous-stem cells could migrate into both injured myocardium and atherosclerotic lesions. If we can elucidate the physiological mechanism of endogenous-stem cell migration, we may be better able to control this process in the future treatment of myocardial injury. Everybody is seeking a chunk of neo-muscle to rebuild diseased heart by cell-based therapy for years. However, no report has shown such a dramatic picture, yet. Further investigation should be focused on not only stem cells but other cells and surrounding components to establish new strategy for endstaged heart failure.