Bone Marrow Stem Cell Therapy Research Articles

Functional Outcome of Bone Marrow Stem Cells (CD45 +/CD34 −) After Cell Therapy in Acute Spinal Cord Injury: In Exercise Training and in Sedentary Rats

Background Cell therapy and exercise training may be options for spinal cord regeneration. Our objective was to evaluate the functional effects of autologous bone marrow stem cell (CD45 +/CD34 −) transplantation in acute spinal cord injury in exercise training and in sedentary rats. Materials and Methods Fifty-five adult male Wistar rats underwent spinal cord contusion by Impactor (NYU). Locomotor rating scale was performed every 48 hours for 48 days. Animals with scores ≤12 were randomly divided into 4 groups: sedentary without parenchymal cell infusion; sedentary with parenchymal cell infusion; swimming training without parenchymal cell infusion; and swimming training with parenchymal cell infusion. Bone marrow stem cells were isolated by puncture-aspiration of the bone marrow and density gradient (d = 1.077). The animals underwent a 60-minute swimming session 6 times/week supporting an overload of 3% of body weight for 6 consecutive weeks. Comparisons between the groups in relation to differences between the beginning to the end of scores used the nonparametric Bonferroni test and post-hoc Mann-Whitney U test to identify significance. Results Forty-two rats that obtained scores ≤12 underwent therapy with 9 animals in each of the 4 groups as completors (n = 36). There was significance ( P ≤ .008) for sedentary without parenchymal cell infusion vs swimming training with parenchymal cell infusion. Conclusion The combination of bone marrow stem cell therapy (CD45 +/CD34 −) and exercise training resulted in significant functional improvement in acute spinal cord injury.

Bones of contention: Marrow-derived cells in myocardial regeneration

Almost 7 years have passed since the initial publication reporting that bone marrow cells regenerate infarcted myocardium. The subsequent years produced hundreds of investigations that ran the gamut of findings from validation to disproof. Undeterred by the concurrent debate, clinical trials ensued to test the safety and efficacy of bone marrow-derived cell population for autologous therapy in clinical treatment of myocardial disease. In the following conversational exchange, two scientists with distinct perspectives weigh the pros and cons of pursuing bone marrow stem cell therapy and look toward finding a consensus of where the future lies for regenerative medicine and the heart. The conclusion is that the two camps may not be as far apart as it may seem from the rancor in literature and at meetings, and the potential of one day achieving regenerative therapy is indeed a vision that both parties enthusiastically share.

Cell therapy in congestive heart failure

Congestive heart failure (CHF) has emerged as a major worldwide epidemic and its main causes seem to be the aging of the population and the survival of patients with post-myocardial infarction. Cardiomyocyte dropout (necrosis and apoptosis) plays a critical role in the progress of CHF; thus treatment of CHF by exogenous cell implantation will be a promising medical approach. In the acute phase of cardiac damage cardiac stem cells (CSCs) within the heart divide symmetrically and/or asymmetrically in response to the change of heart homeostasis, and at the same time homing of bone marrow stem cells (BMCs) to injured area is thought to occur, which not only reconstitutes CSC population to normal levels but also repairs the heart by differentiation into cardiac tissue. So far, basic studies by using potential sources such as BMCs and CSCs to treat animal CHF have shown improved ventricular remodelling and heart function. Recently, however, a few of randomized, double-blind, placebo-controlled clinical trials demonstrated mixed results in heart failure with BMC therapy during acute myocardial infarction.

Lost and found: cardiac stem cell therapy revisited

Several clinical trials of bone marrow stem cell therapy for myocardial infarction are ongoing, but the mechanistic basis for any potential therapeutic effect is currently unclear. A growing body of evidence suggests that the potential improvement in cardiac function is largely independent of cardiac muscle regeneration. A study by Fazel et al. in this issue of the JCI provides evidence that bone marrow-derived c-kit+ cells can lead to an improvement in cardiac function in mutant hypomorphic c-kit mice that is independent of transdifferentiation into either cardiac muscle or endothelial cells, but rather is associated with the release of angiogenic cytokines and associated neovascularization in the infarct border zone (see the related article beginning on page 1865). These findings suggest the potential therapeutic effect of specific paracrine pathways for angiogenesis in improving cardiac function in the injured heart.

The Bone Marrow Functionally Contributes to Liver Fibrosis

Bone marrow (BM) cells may transdifferentiate into or fuse with organ parenchymal cells. BM therapy shows promise in murine models of cirrhosis, and clinical trials of bone marrow stem cell therapy for organ healing are underway. However, the BM may contribute to scar-forming myofibroblasts in various organs including the liver. We have studied this axis of regeneration and scarring in murine models of cirrhosis, including an assessment of the temporal and functional contribution of the BM-derived myofibroblasts. Female mice were lethally irradiated and received male BM transplants. Carbon tetrachloride or thioacetamide was used to induce cirrhosis. BM-derived cells were tracked through in situ hybridization for the Y chromosome. BM transplants from 2 strains of transgenic mice were used to detect intrahepatic collagen production. In the cirrhotic liver, the contribution of BM to parenchymal regeneration was minor (0.6%); by contrast, the BM contributed significantly to hepatic stellate cell (68%) and myofibroblast (70%) populations. These BM-derived cells were found to be active for collagen type 1 transcription in 2 independent assays and could influence the fibrotic response to organ injury. These BM-derived myofibroblasts did not occur through cell fusion between BM-derived cells and indigenous hepatic cells but, instead, originated largely from the BM's mesenchymal stem cells. The BM contributes functionally and significantly to liver fibrosis and is a potential therapeutic target in liver fibrosis. Clinical trials of BM cell therapy for liver regeneration should be vigilant for the possibility of enhanced organ fibrosis.

338 Failure of bone marrow stem cell therapy to improve liver fibrosis in the cci 4 murine model

338 Failure of bone marrow stem cell therapy to improve liver fibrosis in the cci 4 murine model

Mesenchymal Stem Cells for Myocardial Infarction

Recent studies indicate that cardiac transfer of adult stem cells can have a favorable impact on tissue perfusion and contractile performance of the infarcted heart. Several cell sources are being explored in an effort to regenerate infarcted myocardium, including hematopoietic stem cells, endothelial progenitor cells, cardiac resident stem cells, bone marrow–derived multipotent stem cells, and mesenchymal stem cells (MSCs). Each of these cell types may have its own profile of advantages, limitations, and practicability issues in specific settings. Studies comparing the regenerative capacity of distinct cell populations are scarce. Most clinical investigators have therefore chosen a pragmatic approach by using unselected bone marrow cells that contain different stem cell populations. Basic scientists, by contrast, are focusing more on specific cell populations in a quest to understand the biological foundations of cell therapy and to identify the most promising stem cells for cardiac regeneration.1 See p 214 MSCs are a rare population of self-renewing, multipotent cells present in adult bone marrow. Although MSCs represent <0.01% of all nucleated bone marrow cells, they can be readily expanded in vitro. In defined culture media, MSCs differentiate into several mesenchymal cell lineages, including cardiomyocytes.2,3 When injected into normal adult myocardium, MSCs differentiate into cardiomyocyte-like cells with sarcomeric organization.4 In an earlier study in pigs with myocardial infarction (MI), MSCs grafted into the infarcted area were shown to express muscle-specific markers and to improve regional wall motion.5 Ease of isolation, high expansion capability, and cardiomyogenic potential have led to the proposition that MSCs may be a good choice for cell-based therapies of MI.6 In a report published in this issue of Circulation , Dai et al7 have …

Development of a minimally invasive bone marrow harvest device and method for the rapid extraction of bone marrow for use in bone marrow transplantation and stem cell therapy

The bone marrow contains a rich supply of hematopoetic, mesenchymal and other stem cell populations. Bone marrow and peripheral blood–derived hematopoetic stem cells are currently used in> 40,000 bone marrow and peripheral blood stem cell transplants each year worldwide. Adult bone marrow–derived stem cells may soon be used in various stem cell–mediated regenenerative therapies, resulting in an increased need for a simplified, economical acquisition of bone marrow. Allogeneic marrow, or G-CSF mobilized marrow, may prove to be superior to PBSC for several transplantation indications, and thus improved harvest methods are needed.

Effect of Soman Poisoning on Populations of Bone Marrow and Peripheral Blood Cells in Mice

According to recent reports, brain lesions resulting from ischemia, mechanical injury or neurodegenerative diseases can be partially treated using bone marrow-derived stromal cell (BMSC) engraftment approaches. Nevertheless, for brain lesions resulting from organophosphate poisoning, nerve agents such as soman (pinacolyl methylphosphono-fluoridate) could affect blood and bone marrow (BM) micro-environments, thus preventing efficient BMSC migration and engraftment. It is therefore necessary to verify the hematologic response to soman exposure. To assess this issue, the survival of BM cells, in particular hematopoietic progenitor and precursor cells (HPC), as well as distribution of the different populations of peripheral blood cells, were investigated in soman-intoxicated mice. Nine-week-old adult male B6D2F1 mice were treated with 110 μg/kg soman and 5.0 mg/kg methyl nitrate atropine. BM and peripheral blood (PB) samples were collected 1, 4, 8 and 22 days after poisoning. Various parameters were determined such as PB cell counting or, for BM samples, myelogram, in vitro colony-forming cells and phenotypic flow cytometry analysis. On post-soman day 1, a significant decrease in numbers of white blood cells and an increase in erythrocyte and platelet counts were noted. On post-soman day 4, the number of HPC decreased significantly, probably due to reduction of the replication rate of these immature cells. However, the number of more immature cells (Sca1+/Lin− phenotype) remained unchanged. On post-soman day 8 and day 22, the number of monocytes and granulocytes in the blood had considerably increased, probably due to a strong inflammatory reaction in response to soman poisoning. In conclusion, PB cell and BM-derived HPC populations are affected by acute soman poisoning, suggesting particular care, mainly for graft kinetic aspects, during future development of autologous BM stem cell therapy strategy to treat nerve agent-induced brain damage.