Use Of Bone Marrow-derived Cells Research Articles

Cell Therapy for Age-Related Macular Degeneration: A New Vision for the Bone Marrow?

In this issue of Molecular Therapy, Qi et al.1 report that a cell therapy can improve retinal structure and vision in a mouse model of age-related macular degeneration (AMD). AMD is the leading cause of severe and irreversible central vision loss in the elderly, affecting over 1.7 million Americans.2 The authors made use of bone marrow-derived cells (BMDCs) that had been engineered to stably express RPE65 protein (BMDC-RPE65). RPE65 is a marker of the retinal pigment epithelium (RPE) that degenerates in AMD.

One-step bone marrow-derived cell transplantation in talarosteochondral lesions: mid-term results

to verify the capability of scaffold-supported bone marrow-derived cells to be used in the repair of osteochondral lesions of the talus. using a device to concentrate bone marrow-derived cells, a scaffold (collagen powder or hyaluronic acid membrane) for cell support and platelet gel, a one-step arthroscopic technique was developed for cartilage repair. In a prospective clinical study, we investigated the ability of this technique to repair talar osteochondral lesions in 64 patients. The mean follow-up was 53 months. Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) scale score. We also considered the influence of scaffold type, lesion area, previous surgery, and lesion depth. the mean preoperative AOFAS scale score was 65.2 ± 13.9. The clinical results peaked at 24 months, before declining gradually to settle at a score of around 80 at the maximum follow-up of 72 months. the use of bone marrow-derived cells supported by scaffolds to repair osteochondral lesions of the talus resulted in significant clinical improvement, which was maintained over time. level IV, therapeutic case series.

Stem cell therapy for cardiovascular disease: the demise of alchemy and rise of pharmacology

Regenerative medicine holds great promise as a way of addressing the limitations of current treatments of ischaemic disease. In preclinical models, transplantation of different types of stem cells or progenitor cells results in improved recovery from ischaemia. Furthermore, experimental studies indicate that cell therapy influences a spectrum of processes, including neovascularization and cardiomyogenesis as well as inflammation, apoptosis and interstitial fibrosis. Thus, distinct strategies might be required for specific regenerative needs. Nonetheless, clinical studies have so far investigated a relatively small number of options, focusing mainly on the use of bone marrow-derived cells. Rapid clinical translation resulted in a number of small clinical trials that do not have sufficient power to address the therapeutic potential of the new approach. Moreover, full exploitation has been hindered so far by the absence of a solid theoretical framework and inadequate development plans. This article reviews the current knowledge on cell therapy and proposes a model theory for interpretation of experimental and clinical outcomes from a pharmacological perspective. Eventually, with an increased association between cell therapy and traditional pharmacotherapy, we will soon need to adopt a unified theory for understanding how the two practices additively interact for a patient's benefit.

Bone marrow-derived cell therapy in chagasic cardiac disease: a review of pre-clinical and clinical results.

Chagas disease is caused by a protozoan parasite Trypanosoma cruzi, which infects people through blood sucking insects. It is endemic in Latin America and the disease is being spread to developed countries as a result of the migration of infected individuals. In its chronic stage, Chagas disease can lead to a severe cardiomyopathy for which there is currently no cure. End-stage patients require heart transplantation, thus demanding new therapeutic modalities. Cell-based therapy has been proposed as an alternative for various forms of heart disease. Here we review the experimental evidence that led to the use of bone marrow-derived cells in putative therapy for chronic chagasic cardiomyopathy in animal models and in clinical trials, discussing the reasons for failure of the translation of results from mice to men.

Effective mobilisation of bone marrow-derived cells through proteolytic activity: A new treatment strategy for age-related macular degeneration

Selective targeting of bone marrow-derived cells (BMCs) has been heralded as a promising avenue for age-related macular degeneration (AMD) therapeutics. Many researchers have demonstrated that the function of circulating BMCs is related to disease severity in patients with AMD. Transplanted BMCs are able to transdifferentiate into retina-specific cells to replace those lost due to damage or degeneration in the pathologic process of experimental models of AMD, which may provide beneficial effects in patients with AMD. However, a major barrier to transferring the use of BMCs into clinical practice is the limited quantity of BMCs in the peripheral circulation. Technology has not yet reached a stage where ex vivo-expanded BMCs can be routinely used for cell therapy. A feasible strategy to circumvent this issue of BMC scarcity is to increase the mobilisation of autologous BMCs from the patient’s bone marrow into the blood circulation. Extensive studies have demonstrated that the SDF-1/CXCR4 axis is a key regulator for BMC mobilisation. Moreover, abrogation of the SDF-1/CXCR4 axis by proteolytic modification can efficiently increase BMC mobilisation. We speculate that BMC mobilisation by proteolytic enzymes may supply a sufficient amount of autologous cells to repair and regenerate injured and degenerated the retinal pigment epithelium (RPE), photoreceptors, or other retina-specific cells, which could prevent AMD progression. If the BMC mobilisation strategy is used to treat AMD, it may overcome the existing problems of transferring BMC-based therapy into the clinic and become a particularly feasible therapeutic approach for AMD.

Bone Marrow-Derived Cell Transplantation Therapy for Myocardial Infarction: Lessons Learned and Future Questions

Over the last decade, many investigators have utilized bone marrow-derived cells for cell transplantation therapy in animal studies and in patients with acute myocardial infarction and chronic heart failure. In those experimental and clinical studies, various doses and types of bone marrow-derived cells have been transplanted to the injured myocardium using a variety of approaches, such as intracoronary infusion or catheter-based direct endomyocardial injection, and at different time points after successful coronary reperfusion. The reported treatment effects are variable, which may be related to differences in cell type and quantity of transplanted cells, timing and approach of cell transplantation and patient selection. In this review, we summarize and discuss the controversies and questions related to the clinical use of bone marrow-derived cells.

Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: From open field autologous chondrocyte to bone-marrow-derived cells transplantation

The aims of this study are to describe evolution in cartilage repair from open field autologous chondrocyte implantation to regeneration by arthroscopic bone-marrow-derived cells (BMDCs) “one step” technique; to present the results of a series of patients consecutively treated and to compare in detail the different techniques used in order to establish the advantages obtained with the evolution in cartilage regenerative methods. 81 patients (mean age 30 ± 8 years) were evaluated in this study. Patient assessment included clinical AOFAS score, X-rays and MRI preoperatively and at different established follow-ups. All the lesions were >1.5 cm 2 and received open autologous chondrocyte implantation (10 cases), arthroscopic autologous chondrocyte implantation (46 cases), and “one step” arthroscopic repair by BMDC transplantation (25 cases). For arthroscopic repair techniques a hyaluronic acid membrane was used to support cells and specifically designed instrumentation was developed. Patients of all the three groups underwent a second arthroscopy with a bioptic cartilage harvest at 1 year follow-up. Mean AOFAS score before surgery was 57.1 ± 17.2 and 92.6 ± 10.5 ( P < 0.0005) at mean 59.5 ± 26.5 months. A similar pattern of AOFAS improvement in results was found in the three different techniques. Histological evaluations highlighted collagen type II and proteoglycan expression. The cartilage repair techniques described were able to provide a repair tissue which closely approximates the characteristics of the naive hyaline cartilage. Evolution in surgical technique, new biomaterials and more recently the use of BMDCs permitted a marked reduction in procedure morbidity and costs up to a “one step” technique able to overcome all the drawbacks of previous repair techniques.

Stem Cell Therapy : Hype or Hope ?

Cell therapy trials for “regenerating” chronically failing hearts have entailed the use of bone marrow-derived cells and skeletal myoblasts. In the case of bone marrow cells, surgical injections of the mononuclear fraction combined with coronary artery bypass surgery have failed to show any substantial benefit. More successful outcomes have been reported after catheter transfer of these cells or intraoperative epicardial injections of CD133+ progenitors, probably because of angiogenesis. In the case of skeletal myoblasts, the surgical MAGIC trial has not achieved its primary efficacy end point but the highest dose of myoblasts resulted in a significant anti-remodeling effect compared with the placebo group. The results of the catheter-based myoblast delivery trials have been more disappointing.

Repeated Courses of Bone Marrow-Derived Cell Mobilization Induced by Granulocyte-Colony Stimulating Factor (G-CSF) in Amyotrophic Lateral Sclerosis: Interim Analysis of a Prospective Multicenter Trial.

Background. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder of the adult life, characterized by the progressive loss of cortical and spinal motor neurons and an outcome usually fatal within 3 to 5 yrs, due to respiratory failure, with no effective therapies presently available. Efforts are needed in ALS to find novel treatments, able to reduce or block neuronal loss and/or to rebuild damaged neuronal circuits. Recent studies have raised the interest for the use of bone marrow-derived cells (BMCs) to repair damaged nervous system; this approach seems particularly attractive in ALS, which is characterized by neuronal degeneration. Aims of the study. To evaluate, at the multicenter setting, feasibility, safety and tolerability, and possible benefit of repeated procedures of G-CSF-induced BMC mobilization in ALS patients.Patients and methods. Seven Neurology Centers, along with seven Hematology Centers, are participating to the multicenter “STEMALS” trial, that started in June 2006 and will enrol a total of 28 patients, with 4 mobilization procedures for each patients; this is the interim analysis, after 42 mobilization procedures performed on a total of 22 patients. Patient median age is 56 yrs (range 40–64), 14 are male. The protocol includes four cycles of G-CSF, scheduled at 3 mos. intervals. In each cycle, G-CSF is administered at the dose of 5 μg/kg s.c., twice a day, for 4 consecutive days. At each cycle, CBCs and circulating CD34+ cells are determined, since day 0 through day 6.Results. Overall, 18 patients completed the first G-CSF cycle and all displayed good response; peak values were for WBCs: 41 x103/μL (range 24– 71) at day 3, and for CD34+ve cells: 52/μL (range 8.4–156), at day 4; 16 patients have already completed the second mobilization course, with values of circulating cells matching those of the first cycle (median WBCs/μL: 42x103; median CD34+ve/μL: 60.7); a few patients have undergone the third and fourth cycle, again they consistently displayed high levels of mobilization. Overall, the mobilization procedures were well tolerated, with the exception of a transient increase of growth hormone level in one patient, and a deep venous thrombosis in one patient, both complications did not preclude to conclude the treatment.Conclusion. The STEMALS trial indicate that: i. the use of G-CSF to induce BMC mobilization is safe, well tolerated and feasible in ALS, even at the multicenter level; ii. so far, few and reversible adverse effects have been recorded; iii. peak values of circulating CD34+ve cells indicate that BMC mobilization capacity in ALS is analogous to that commonly observed in the healthy population; iv. there are no signs of impaired mobilization, after repeated courses of G-CSF administration, performed at few month intervals. A longer follow up is still required to verify possible benefits of the repeated BMC mobilization program in ALS.

Hyaluronan Mixed Esters of Butyric and Retinoic Acid Drive Cardiac and Endothelial Fate in Term Placenta Human Mesenchymal Stem Cells and Enhance Cardiac Repair in Infarcted Rat Hearts

We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure.

Bone marrow cell infusion ameliorates progressive glomerulosclerosis in an experimental rat model

Bone marrow (BM) cells contribute to the maintenance and repair of several compartments of the kidney, including the endothelium, interstitium, epithelium, and the mesangium. The aim of this study was to explore the therapeutic use of bone marrow-derived cells (BMDC) that can differentiate into endothelial and mesangial cells in a model of progressive glomerulosclerosis. To investigate the involvement of BMDC in glomerular repair, progressive glomerulosclerosis was induced in enhanced green fluorescent protein BM chimeric rats by a one-shot injection of anti-Thy-1.1 monoclonal antibody, followed by unilateral nephrectomy. Subsequently, these rats were treated with either a BM cell infusion or phosphate-buffered saline. Renal function, intravital glomerular hemodynamics, and histological alterations were examined 12 weeks after anti-Thy-1.1 monoclonal antibody injection. Inflammatory infiltration of macrophages in the kidneys was evaluated by immunofluorescence of ED-1. We also determined whether BMDC contributed to repair and regeneration of endothelial and mesangial cells by immunofluorescence monitoring. As a result, BM cell infusion improved renal function and glomerular hemodynamics, and histological alterations with reduced glomerular infiltration of macrophages, leading to dramatically reduced mortality in this model of progressive glomerulosclerosis. We also demonstrated that, in the BM cell infusion group, more BMDC contributed to repair and regeneration of endothelial and mesangial cells than in the untreated group. The present study provides us with a conceptual basis for the development of therapeutic stem cell strategies aimed at enhancing recovery from progressive glomerulosclerosis.

114. Efficient Arterial Formation at the Sites of Adult Neo-Angiogenesis Requires the Recruitment of Bone Marrow Cells through the Neuropilin-1 (NP-1) Receptor

The potential use of bone marrow-derived cells (BMCs) to promote new blood vessel formation, recapitulating vasculogenesis in the adult, has recently aroused much excitement, and a rapid transposition to the clinic. However, new experimental evidence has challenged this notion, demonstrating that BMCs transplanted into ischemic tissues still adopt mature hematopoietic fates and do not transdifferentiate into vascular structures. To better define the actual role of bone marrow-derived cells in the formation of new blood vessels, we developed a series of AAV vectors to drive the persistent expression of several factors, differing in their capacity to promote angiogenesis and to recruit BMCs.

Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord.

Mesenchymal stem cells (MSCs) have the capability for renewal and differentiation into various lineages of mesenchymal tissues. These features of MSCs attract a lot of attention from investigators in the context of cell-based therapies of several human diseases. Despite the fact that bone marrow represents the main available source of MSCs, the use of bone marrow-derived cells is not always acceptable due to the high degree of viral infection and the significant drop in cell number and proliferative/differentiation capacity with age. Thus, the search for possible alternative MSC sources remains to be validated. Umbilical cord blood is a rich source of hematopoietic stem/progenitor cells and does not contain mesenchymal progenitors. However, MSCs circulate in the blood of preterm fetuses and may be successfully isolated and expanded. Where these cells home at the end of gestation is not clear. In this investigation, we have made an attempt to isolate MSCs from the subendothelial layer of umbilical cord vein using two standard methodological approaches: the routine isolation of human umbilical vein endothelial cell protocol and culture of isolated cells under conditions appropriate for bone-marrow-derived MSCs. Our results suggest that cord vasculature contains a high number of MSC-like elements forming colonies of fibroblastoid cells that may be successfully expanded in culture. These MSC-like cells contain no endothelium- or leukocyte-specific antigens but express alpha-smooth muscle actin and several mesenchymal cell markers. Therefore, umbilical cord/placenta stroma could be regarded as an alternative source of MSCs for experimental and clinical needs.