Cell transplantation has come of age but numerous questions still remain. Which type of cell should be used? Cardiac precursors are present in mouse bone marrow and used to repair the infarcted myocardium in mice. We searched for these precursors in human bone marrow and analyzed gene expression patterns in cells induced to differentiate in vitro.
Cells from human bone marrow were isolated and cultured in medium supplemented with autologous serum and 5% CO2. Cell characterization was performed by immunocytochemical analysis. mRNA was isolated and retrotranscribed. The active genes were detected with polymerase chain reaction by using specific oligonucleotides.
Some inducers pushed the cell through different stages of cardiogenesis, with expression of cardiac transcriptional activators and structural proteins. Some combinations of stimuli were able to drive cells to advanced stages of cardiogenesis.
These studies lead to an exact description of in vitro cardiogenesis in humans. Our aim was also to assess the residual proliferative capacity of cells and to enhance the differentiation efficiency, thus maximizing their repair capacity and the likelihood that they functionally integrate with the surrounding cardiac tissue.
[Show abstract][Hide abstract] ABSTRACT: Tissue engineering combines the principles of medical, life science, and engineering fields toward the development of biological substitutes to restore, maintain, or improve tissue function. Previous work has demonstrated the feasibility of bioengineering smooth muscle tissue in vitro; however the contractile properties of bioengineered smooth muscle tissue have not been evaluated. It is imperative that bioengineered tissues have a high degree of functional testing in order to evaluate tissue-specific function as well as suitability for future clinical applications. This research describes the development and functional testing of novel 3-dimensional bioengineered smooth muscle tissues in vitro and the development of a micro-perfusion system to support culture and enhance functionality of bioengineered tissues. All bioengineered tissue models described here were developed utilizing a fibrin biomaterial, which is well-suited for bioengineering contractile tissues. We developed ring-shaped models of rat sphincter and colonic smooth muscle tissue as well as a strip model of human aortic vascular smooth muscle tissue. Functional testing of the contractile properties of bioengineered muscle tissues was accomplished using a custom build force transducer. Bioengineered tissues exhibited striking tissue-specific functionality, which was similar to smooth muscle in vivo, including the generation of spontaneous basal tone and agonist-induced contraction and relaxation, which was calcium-dependent and calcium-independent (respectively). Finally, in order to support the increased metabolic demands of bioengineered tissues, we designed and fabricated a novel micro-perfusion system to promote delivery of a constant supply of oxygenated media to bioengineered tissues. We tested the compatibility of our micro-perfusion system with Bioengineered Heart Muscle (BEHM) and found that the system is capable of supporting viability (mitochondrial activity, total protein, total RNA) and maintaining contractile properties (twitch force, specific force, electrical pacing, and expression of contractile proteins) of bioengineered tissues. In addition, short-term exposure of BEHMs to micro-perfusion resulted in some functional improvement. This research specifically adds to the knowledge base of two critical areas in tissue engineering research: 1) the development of functional bioengineered models, and 2) ancillary technology to support these models. Collectively, this research bridges several scientific and technological gaps in the field of functional tissue engineering. Ph.D. Applied Physics University of Michigan, Horace H. Rackham School of Graduate Studies http://deepblue.lib.umich.edu/bitstream/2027.42/58465/1/lhecker_1.pdf
[Show abstract][Hide abstract] ABSTRACT: The ischemia-induced death of cardiomyocytes results in scar formation and reduced contractility of the ventricle. Several preclinical and clinical studies have supported the notion that cell therapy may be used for cardiac regeneration. Most attempts for cardiomyoplasty have considered the bone marrow as the source of the "repair stem cell(s)," assuming that the hematopoietic stem cell can do the work. However, bone marrow is also the residence of other progenitor cells, including mesenchymal stem cells (MSCs). Since 1995 it has been known that under in vitro conditions, MSCs differentiate into cells exhibiting features of cardiomyocytes. This pioneer work was followed by many preclinical studies that revealed that ex vivo expanded, bone marrow-derived MSCs may represent another option for cardiac regeneration. In this work, we review evidence and new prospects that support the use of MSCs in cardiomyoplasty.
Experimental Biology and Medicine 02/2006; 231(1):39-49. · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances in stem cell biology have given rise the new field of cardiac regenerative medicine. Specifically, the development of cardiac stem cell science now offers the promise of novel cardiovascular therapies based on a dynamic body of basic and translational research. Importantly, the potential wide-spread clinical application of this technology will require that therapies be optimized for individuals with potential impairments in cardiac stem cell function. To this end, the previous experience of hematopoietic stem cell therapies can provide important guidance in the development and maturation of the young cardiac stem cell field. Parallel to the impact that exogenous growth factors have made in the field of hematopoietic therapies, the discovery and potential application of the factor(s) that govern cardiac regeneration may speed the progression of cardiac stem cell technology into an assessable and potent clinical therapy.
Regenerative Medicine 04/2006; 1(2):217-21. DOI:10.2217/174607184.108.40.206 · 2.79 Impact Factor
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