Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell-derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell-derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.

https://courses.washington.edu/conj504/readings/murry_reading2.pdf

Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. To identify a source of stem cells capable of restoring damaged cardiac tissue, we transplanted highly enriched hematopoietic stem cells, the so-called side population (SP) cells, into lethally irradiated mice subsequently rendered ischemic by coronary artery occlusion for 60 minutes followed by reperfusion. The engrafted SP cells (CD34–/low, c-Kit+, Sca-1+) or their progeny migrated into ischemic cardiac muscle and blood vessels, differentiated to cardiomyocytes and endothelial cells, and contributed to the formation of functional tissue. SP cells were purified from Rosa26 transgenic mice, which express lacZ widely. Donor-derived cardiomyocytes were found primarily in the peri-infarct region at a prevalence of around 0.02% and were identified by expression of lacZ and α-actinin, and lack of expression of CD45. Donor-derived endothelial cells were identified by expression of lacZ and Flt-1, an endothelial marker shown to be absent on SP cells. Endothelial engraftment was found at a prevalence of around 3.3%, primarily in small vessels adjacent to the infarct. Our results demonstrate the cardiomyogenic potential of hematopoietic stem cells and suggest a therapeutic strategy that eventually could benefit patients with myocardial infarction.

/pdf/regeneration-of-ischemic-cardiac-muscle-and-vascular-316hhyyzvm.pdf

Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells

Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development.

Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts

http://www.kumc.edu/Documents/msctc/Mangi-Nat%20Med.%20(2003).pdf

Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction

Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies.

Background—Cardiomyocyte grafting augments myocyte numbers in the heart. We investigated (1) how developmental stage influences graft survival; (2) whether acutely necrotic or healing cardiac lesions support grafts; and (3) the differentiation and integration of cardiomyocyte grafts in injured hearts. Methods and Results—Cardiomyocytes from fetal, neonatal, or adult inbred rats were grafted into normal myocardium, acutely cryoinjured myocardium, or granulation tissue (6 days after injury). Adult cardiomyocytes did not survive under any conditions. In contrast, fetal and neonatal cardiomyocytes formed viable grafts under all conditions. Time-course studies with neonatal cardiomyocytes showed that the grafts recapitulated many aspects of normal development. The adherens junction protein N-cadherin was distributed circumferentially at day 1 but began to organize into intercalated disk–like structures by day 6. The gap junction protein connexin43 followed a similar but delayed pattern relative to N-cadherin. ...

http://staff.washington.edu/hreineck/Circ99.pdf

Survival, Integration, and Differentiation of Cardiomyocyte Grafts A Study in Normal and Injured Rat Hearts

Despite impressive advances in the last decade at treating coronary atherosclerosis, myocardial infarction remains the number one cause of death and disability in industrialized countries A great deal of effort has been expended over the last 25 years toward identifying strategies to limit the amount of myocardium lost to infarction [4, 5] Although infarct size limitation remains a highly desirable goal, it has been extremely difficult to achieve clinically Over the last 5 years, our group has become increasingly interested in working on strategies to enhance the repair phase of myocardial infarction [31-33, 42, 43] Our long-term goals are to induce muscular regeneration of the infarcted region An intermediate goal, however, is to understand the molecular biology of infarct healing and to find strategies to prevent complications of infarction such as ventricular dilation that contribute to heart failure This chapter will review the pathobiology of myocardial infarction and infarct repair, and then summarize some of our recent work in cardiomyocyte transplantation for creation of new myocardium

Ming Zhang

Papers

Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies.

Survival, Integration, and Differentiation of Cardiomyocyte Grafts A Study in Normal and Injured Rat Hearts

Myocardial infarction, infarct repair, and strategies for muscle regeneration