Update cardiac stem cell therapy

Chronic ischemic heart disease remains one of the most important causes of morbidity and mortality worldwide. Although revascularisation procedures and conventional drug therapy may delay ventricular remodelling, there is no basic therapeutic regime available to prevent or even reverse this process. Chronic coronary artery disease and heart failure impair quality of life and are associated with subsequent worsening of left ventricular function. In the recent past experimental and clinical studies have demonstrated the capacity of bone marrow stem cells in cardiac repair and regeneration of compromised heart muscle. Several clinical trials showed the safety and efficacy of autologous bone marrow stem cell transplantation in the patients with acute myocardial infarction or chronic ischemic heart disease. Today the therapeutic strategy of cell administration during cardiac surgery or coronary artery intervention is entering the clinical practice. Biological as well as methodological backgrounds, indications and clinical results of cardiac stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease are reviewed.     

骨髓单个核细胞移植治疗缺血性心脏病的进展

骨髓单个核细胞包括间充质干细胞、造血干细胞和内皮祖细胞,这些细胞移植到缺血心肌后可分化为心肌细胞、血管内皮细胞和平滑肌细胞;并且可通过旁分泌和自分泌一些细胞因子促进血管新生,防止宿主细胞和移植细胞凋亡,并使内源性修复细胞归巢,修复受损的心肌。目前国内外已进行了大量应用于缺血性心脏病的试验,这些研究采用多种途径将骨髓单个核细胞植入到冠状动脉或心肌内,包括冠状动脉内注射、静脉输入、直接室壁注射、心外膜或心内膜下输入,并通过将细胞制成碎片而提高其滞留率,或应用一些细胞因子提高治疗效果。虽然目前这些临床试验结果尚存在争议,但这些方法在治疗缺血性心脏病方面仍有前景。现对骨髓单个核细胞移植治疗缺血性心脏病的机制、移植途径、骨髓单个核细胞的滞留、归巢、存活和展望等进行综述。     

Frontiers in nephrology: the evolving therapeutic applications of endothelial progenitor cells

Cardiovascular-renal diseases are the leading causes of death and disability in the modern world. Moreover, chronic heart failure after myocardial infarction and peripheral arterial disease are predominant, devastating cardiovascular entities that limit prognosis and greatly impair quality of life in patients despite modern medical treatments. Cardiovascular diseases are also the predominant cause of death in people with renal diseases, underscoring the close relationship between these diseases. Until recently, medical efforts aimed only at prevention and slowing of functional deterioration after organ damage; however, the recent discovery of endogenous repair mechanisms involving hematopoietic stem and other progenitor cells has challenged the long-standing dogma regarding the inability to repair or regenerate terminally differentiated organs. A variety of stem and progenitor cell populations have shown properties that are potentially suited for tissue repair. After encouraging results in preclinical animal models, early clinical studies of endothelial progenitor cells (EPC) have begun. Envisioning the goal of true tissue regeneration, application of bone marrow-derived progenitors for heart and limb ischemia has provided early evidence of safety and feasibility. These studies have provided data indicating functional improvement as well. Although there is strong experimental and clinical evidence for a regenerative function of EPC even in renal disease, there has been no clinical application of this approach. After the initial flurry of activity, it is time to reconsider these approaches and attempt to optimize functional improvement and patient safety. This article briefly recapitulates biologic and functional characteristics of EPC before giving a concise overview on current therapeutic EPC applications in the field of cardiovascular-renal medicine with consideration of future challenges.     

Stem cell therapy for ischemic heart disease: beginning or end of the road?

Despite improvements in emergency treatment, myocardial infarction is often the beginning of a downward spiral leading to congestive heart failure. Other than heart transplantation, current therapeutic means aim at enabling the organism to survive with a heart that is working at a fraction of its original capacity. It is therefore no surprise that cardiac stem cell therapy has raised many hopes. However, neither the ideal source and type of stem cell nor the critical cell number and mode of application have been defined so far. Early reports on myocardial repair by adult bone marrow stem cells from rodent models promoted an unparalleled boost of clinical and experimental cell therapy studies. The phenomenon of stem/progenitor cell-induced angiogenesis in ischemic myocardium has ever since been reproduced by numerous groups in a variety of small and large animal models. Myogenesis, however, is an altogether different matter. Many of the initial clinical studies were fueled by the suggestion that early hematopoietic stem cells have a plasticity high enough to enable cross-lineage differentiation into cells of cardiomyocyte phenotype, but the initial enthusiasm has largely faded. The myogenic potential of stroma cell-derived mesenchymal stem cells is much better documented in animal models, but transfer to the clinical setting faces a variety of obstacles. In clinical pilot trials, we and others have demonstrated the feasibility and safety of administering progenitor cells derived from autologous bone marrow to the myocardium of patients with ischemic heart disease. Clinical efficacy data are still rare, but the few controlled trials that have been completed uniformly show a tendency towards better heart function in cell-treated patients. This review is an attempt to describe the scientific basis for cardiac cell therapy from the point of view of the clinician, focusing on problems that arise with beginning translation into the clinical setting.     

Bone marrow cell therapies for endothelial repair and their relevance to kidney disease

Endothelial injury is a characteristic finding in chronic kidney disease and is associated with both markedly increased cardiovascular risk and chronic kidney disease progression. The past decade has seen a remarkable surge of interest in the role of bone marrow-derived cells for the protection, repair, and regeneration of injured endothelium. In particular, despite controversies regarding their mechanisms of action, endothelial progenitor cells have garnered considerable attention, with multiple reports suggesting that these cells exhibit remarkable pro-angiogenic effects. Recent advances in our understanding of how the bone marrow responds to endothelial injury now suggest that multiple bone marrow cell populations, including both endothelial progenitor cells and a novel group of cells called early outgrowth cells, promote endothelial repair and regeneration through different, yet complementary, mechanisms. Moreover, certain subsets of bone marrow-derived cells also appear to have novel, potent, angiogenesis-independent tissue-protective properties. The bone marrow should thus now be viewed not only as a hematopoiesis organ, but also as a rich reservoir of cells capable of protecting and even regenerating nonhematopoietic tissues such as the kidney. To harness the prognostic and therapeutic potential of the bone marrow, the renal community must be aware of recent advances in our understanding of the nature and therapeutic potential of these cells.     

The coronary delivery of marrow stromal cells for myocardial regeneration: pathophysiologic and therapeutic implications

OBJECTIVES: Bone marrow stromal cells contain "adult stem cells." We tested the hypothesis that coronary-infused bone marrow stromal cells may populate the infarcted heart and undergo milieu-dependent differentiation to regenerate functional tissues with different phenotypic features. METHODS: Isogenic adult rats were used as donors and recipients to simulate autologous transplantation clinically. Myocardial infarction was created by proximal occlusion of left coronary artery in 12 recipient rats. Isolated bone marrow stromal cells were purified, expanded, and retrovirally transduced with LacZ reporter gene for cell labeling. Stromal cells were then infused into the briefly distally clamped ascending aorta of recipient rats 2 weeks after left coronary artery ligation. The hearts were harvested immediately (n = 2) or 4 weeks (n = 10) later to trace the implanted cells and identify their phenotypes. RESULTS: Viable cells labeled with LacZ reporter gene were identified in 8 recipient hearts. Immediately after cell infusion, the labeled cells were trapped within the coronary capillaries. After 4 weeks, they could be detected individually or in clusters within myocardial scar expressing fibroblastic phenotype or outside the infarction area with morphologic features of normal cardiomyocytes. Some were incorporated into endocardium and capillary endothelium. CONCLUSIONS: Our findings suggest that bone marrow stromal cells can traffic through the coronary system to the injured heart and form cardiomyocytes or fibroblasts, depending on the specific microenvironment. Endothelial progenitor cells in the stromal cell population may be involved in the postinfarction neovascularization process. Whether therapeutic use of bone marrow stromal cells can improve the myocardial healing and remodeling process after infarction is worthy of further investigation.     

Cell-based therapeutic angiogenesis for the treatment of ischemic disease

Cell-based therapy has been the recent focus of attention for repairing injured organs. Several cell sources, derived from peripheral blood, bone marrow, or embryonic stem cells, have been used to induce angiogenesis successfully in various experimental ischemic models, which might be related to angiogenic cytokine production and endothelial incorporation from implanted cells within the targeted ischemic tissues after implantation. Clinical trials have also reported the feasibility and found some efficacy of therapeutic angiogenesis induced by the implantation of autologous bone marrow-(or peripheral blood)-derived cells in patients with ischemic heart disease and peripheral artery disease. Although many questions regarding the effectiveness and safety, optimal cell number and route of delivery, and mechanisms remain, cell-based therapeutic angiogenesis may be a novel and promising treatment option for ischemic disease.     

Intramyocardial CD34+ cell transplantation combined with off-pump coronary artery bypass grafting

This report describes a new therapeutic approach for severe ischemic heart disease, intramyocardial transplantation of autologous bone marrow-derived CD34 + cells combined with off-pump coronary artery bypass grafting (CABG). CD34 is widely known as a cell surface antigen expressed on hematopoietic stem cells, and recent experimental studies have shown that CD34 + cells include endothelial progenitor cells. We used the Isolex 300i magnetic cell selection system to separate CD34 + cells from bone marrow cells. This report describes the first case treated with the combination of off-pump CABG and cell transplantation for therapeutic angiogenesis and myocardial regeneration. The transplantation of autologous bone marrow-derived CD34 + cells improved perfusion of the ungraftable ischemic area.     

Intrarenal injection of bone marrow-derived angiogenic cells reduces endothelial injury and mesangial cell activation in experimental glomerulonephritis

Loss of glomerular endothelial cells has been suggested to contribute to the progression of glomerular injury. Although therapeutic angiogenesis induced by administration of bone marrow-derived endothelial progenitor cells has been observed in disease models of endothelial injury, the effects on renal disease have not been clarified. Whether administration of culture-modified bone marrow mononuclear cells would mitigate the glomerular endothelial injury in anti-Thy1.1 nephritis was investigated. After cultivation under conditions that promote endothelial progenitor cell growth, bone marrow mononuclear cells were labeled with CM-DiI, a fluorescence marker, and injected into the left renal artery of Lewis rats with anti-Thy1.1 glomerulonephritis. The decrease in glomerular endothelial cells was significantly attenuated in the left kidney, as compared with the right, in nephritic rats that received the cell infusion. Glomerular injury score, the area positive for mesangial alpha-smooth muscle actin, and infiltration of macrophages were significantly decreased in the left kidney. CM-DiI-positive cells were distributed in glomeruli of the left kidney but not in those of the right kidney. Among CM-DiI-labeled cells incorporated into glomeruli, 16.5 +/- 1.2% of cells were stained with an endothelial marker, rat endothelial cell antigen-1. Culture-modified mononuclear cells secreted 281.2 +/- 85.0 pg of vascular endothelial growth factor per 10(5) cells per day. In conclusion, intra-arterial administration of culture-modified bone marrow mononuclear cells reduced endothelial injury and mesangial activation in anti-Thy1.1 glomerulonephritis. Incorporation into the glomerular endothelial lining and production of angiogenic factor(s) are likely to contribute to the protective effects of culture-modified mononuclear cells against glomerular injury.     

Risk factors for coronary artery disease, circulating endothelial progenitor cells, and the role of HMG-CoA reductase inhibitors

Recent studies suggest that postnatal neovascularization relies not exclusively on sprouting of preexisting vessels ("angiogenesis"), but also involves the contribution of bone marrow-derived circulating endothelial progenitor cells (EPCs). EPCs can be isolated from peripheral blood or bone marrow mononuclear cells, CD34(+) or CD133(+) hematopoietic progenitors. Infusion of EPCs was shown to promote postnatal neovascularization of ischemic tissue after myocardial infarction in animal models and initial clinical trials. Moreover, circulating endothelial precursor cells can home to denuded arteries after balloon injury and contribute to endothelial regeneration, thereby limiting the development of restenosis. Thus, circulating endothelial cells may exert an important function as endogenous repair mechanism to maintain the integrity of the endothelial monolayer and to promote ischemia-induced neovascularization. However, risk factors for coronary artery disease, such as diabetes, hypercholesterolemia, and hypertension are associated with impaired number and function of EPC in patients with coronary artery disease. Therapeutically, the reduction of EPC number and the decreased functional activity in patients with coronary artery disease was counteracted by 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors (statins), vascular endothelial growth factor (VEGF), estrogen, or exercise. At the molecular level, these factors are well established to activate the phosphatidyl-inositol-3-kinase (PI3K)-Akt-dependent activation of the endothelial nitric oxide synthase (eNOS), suggesting that the PI3K-Akt-eNOS signaling pathway may be involved in the transduction of atheroprotective factors. Taken together, the balance of atheroprotective and proatherosclerotic factors may influence EPC levels and their functional capacity to improve neovascularization and endothelial regeneration.     

Role of mesenchymal stromal cells in solid organ transplantation

Mesenchymal stromal cells (MSCs) originally isolated from bone marrow have been derived from almost every tissue in the body. These multipotent cells can be differentiated in vitro and in vivo into various cell types of mesenchymal origin, such as bone, fat, and cartilage. Furthermore, under some experimental conditions, these cells can differentiate into a wider variety of cell types. Upon systemic administration, ex vivo expanded MSCs preferentially home to damaged tissues and participate in regeneration processes through their diverse biological properties. In vitro and in vivo data suggest that MSCs have low inherent immunogenicity and modulate/suppress immunologic responses through interactions with different immune cells. Ease of isolation and ex vivo expansion of MSCs, combined with their intriguing differentiation and immunomodulatory potential, and their impressive record of safety in clinical trials make these cells prime candidates for cellular therapy. Mesenchymal stromal cells derived from bone marrow are currently being evaluated for a wide range of clinical applications including for treatment of immune dysregulation disorders such as acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. In the future, MSCs might potentially provide novel therapeutic options for treatment/prevention of rejection and/or repair of organ allografts through their multifaceted properties.     

Current status of intramyocardial bone marrow stem cell transplantation

Since the first reports of the capacity of bone marrow stem cells for use in cardiac repair and regeneration after acute myocardial infarction, today, the therapeutic strategy of direct cell administration during cardiac surgery is entering clinical practice. Here we report on the current knowledge of the "new cellular tool" in the cardiac surgeon's hands that is enabling them to exceed the limits of modern methods for myocardial revascularization and repair in cardiac surgery. Therefore, we discuss preclinical data focusing on bone marrow stem cell types and point to the current mechanistic explanation of their effects. With 7 years' experience after completing Phase I and Phase II clinical trials with cardiac transplantation of autologous intramyocardial bone marrow stem cells, we draw conclusions about surgical applicability, safety, and efficacy. At present, the functional effects of this treatment are highly promising to become a standard treatment. Further clarification by prospective randomized clinical Phase III trials is necessary in this field.     

Cardiac cell-based therapy: cell types and mechanisms of actions

Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.     

Prepare cells to repair the heart: mesenchymal stem cells for the treatment of heart failure

Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells (MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogenously transplanted MSC migrate and participate in cardiac repair. Based on these findings, several clinical trials have just been started to evaluate the safety and efficacy of MSC for the treatment of heart failure.     

Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans

Stem cell transplants into damaged myocardium may have the potential to improve cardiac function. We investigated the safety of transplanting unmanipulated autologous bone marrow into infarcted myocardium of patients undergoing coronary bypass surgery and assessed its efficacy to improve cardiac function. Fourteen patients with one or more areas of transmural myocardial infarction were studied. Autologous bone marrow was obtained by sternal bone aspirate at the time of surgery, diluted in autologous serum at a ratio of 1:2, and then injected 1 cm apart into the mid-depth of the left ventricular scar. There were no deaths, no perioperative myocardial infarctions, and no significant ventricular arrhythmias. Dobutamine stress echocardiography demonstrated overall improvement in the global and regional left ventricular function 6 weeks and 10 months after surgery. Of 34 infarcted left ventricular segments, 11 were injected with bone marrow alone, 13 were revascularized with a bypass graft alone, and 10 received bone marrow transplantation and a bypass graft in combination. Only the left ventricle segmental wall motion score of the areas injected with bone marrow and receiving a bypass graft in combination improved at low dose and at peak dobutamine stress. These findings suggest that transplantation of unmanipulated autologous bone marrow into scar tissue of the human heart is safe and enhances cardiac function only when used in combination with myocardial revascularization. This benefit can be seen after 6 weeks of the bone marrow transplant and is maintained after 10 months of follow-up.     

Stem cell research and cell transplantation for myocardial regeneration.

Several human organs are not capable of functional regeneration following a tissue defect and react with scar formation. In stem cell transplantation, undifferentiated or partly differentiated precursor cells are applied to defective tissue for therapeutic regeneration. After promising preclinical investigations, the transplantation of autologous stem cells for myocardial infarction treatment is being transferred to clinical use. Mesenchymal stem cells and endothelial precursor cells derived from the bone marrow or circulating blood as well as skeletal myoblasts are employed in clinical trials. Furthermore, indications for cell transplantation and delivery routes vary considerably throughout current investigations. Initial results suggest a potential for restoration of cardiac function in stem cell-treated patients; however, the mechanisms are not fully understood. This overview will focus on objectives, recent achievements, and future perspectives of diverse stem cell transplantation approaches.     

冠状动脉旁路移植术同期经旁路血管移植自体干细胞治疗缺血性心衰

目的 评价冠状动脉旁路移植手术同期经旁路血管移植自体骨髓干细胞治疗缺血性心衰的可行性和安全性.方法 40例需外科手术治疗的陈旧性心梗伴左室功能不全病人,在冠状动脉旁路移植手术同期经旁路血管移植自体骨髓单个核细胞.结果 全组手术死亡1例.手术早期无心梗发生,无肝、肾功能衰竭,无新发恶性心律失常.结论 冠状动脉旁路移植术同期经旁路血管移植自体骨髓单个核细胞治疗冠心病陈旧心梗,为缺血性心衰病人提供了一个全新的综合治疗选择.     

Endothelial progenitor cells: precursors for angiogenesis

The presence of endothelial progenitor cells has been demonstrated in the bone marrow and systemic circulation of adults, thus raising the possibility of a novel strategy to induce therapeutic angiogenesis for ischemic arterial disease. Successful incorporation into sites of actively occurring angiogenesis in numerous animal models has accelerated the enthusiasm for exploiting their therapeutic capacity in humans and has led to the recent use of putative endothelial precursor cells in phase I feasibility and safety studies. However, key biological issues remain ill defined. The relative contribution of these cells to postnatal physiological and pathological neovascularization has not been fully characterized. Furthermore, the molecular phenotype of the putative endothelial progenitor cell and the processes leading to their mobilization from the bone marrow and homing to sites of angiogenesis have yet to be elucidated. This review addresses these fundamental issues that warrant further basic investigation before the full therapeutic potential of these cells can be achieved within appropriate target patients.     

Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model

OBJECTIVES: To assess, using an in vivo engraftment strategy combining bone marrow cell (BMC) transplantation and tissue cardiomyoplasty, the functional outcome of distinct vascular progenitor cell therapy (endothelial progenitor (EPC) and mesenchymal stem (MSC) cells) at distance of myocardium infarction (MI). The study was also designed to test whether scaffold mixing progenitors with unfractionated BMC could improve progenitor recruitment in the damaged myocardium. METHODS: To track engrafted progenitor cells in vivo, cultured murine MSC and EPC were transduced with eGFP lentiviruses. Thirty days after cryogenical induction of MI, C57BL/6J mice were randomized to receive muscle patch placement coated or not (control group), labeled EPC or MSC mixed to the ration of 1:10, or not with unfractionated BMC. Two weeks after transplantation, cardiac function was recorded and heart sections were examined to detect GFP-labeled progenitor cells and analyze cell differentiation. RESULTS: This study showed that either type of mono cell therapy improved angiogenesis and cell survival in the scar but only MSC exhibited the capacity to invade the scar. We found no evidence of myocardial or vascular regeneration from progenitor cells. Engraftment of the progenitors/unfractionated BMC mix increased repopulation and thickness of the scar. CONCLUSION: Combined therapy with unfractionated BMC and expanded MSC appeared thus promising for scar repopulation.