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Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell-derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.

It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.

In this study, the authors use measures of carbon-14 in neuronal DNA from human stroke patient cortical tissue samples to show that, unlike previous studies done in rodents, they do not find any evidence of increased neurogenesis after an ischemic injury. In addition, DNA damage assays suggest that there is no increase in DNA rearrangement after this insult. It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test–derived 14 C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.

Cardiovascular disease is the largest cause of morbidity and mortality in the Western World. Disease progression often involves a loss of contracting cells, cardiomyocytes, which leads to cardiac failure and the need for heart transplantation with time. However the shortage of donor hearts is a large problem and a strong motivator for finding alternative solutions; this is the focus of regenerative heart medicine. For new treatment strategies to be effective we first need to better understand the potential and capacity of the heart and its cells.This thesis addresses two questions specifically: 1) Do cardiomyocytes renew in human hearts during healthy aging? 2) How does cardiac disease affect cardiomyocyte renewal? Studies in experimental animals and to a small extent in humans had previously not been able to resolve these questions, mainly because limitations in methods and ethical restrictions. We employed primarily two methodologies, 14 birth dating and mathematical modeling. 14 birth dating is a method developed within the Frisén group that exploits the changes in atmospheric 14 levels due to testing of nuclear weapons during the Cold War. The 14 concentration in the genomic DNA of a cell reflects when the cell was born, and hence the level of renewal. The core part of the mathematical model is a first order partial differential equation (PDE). It describes cells according to their age and how the distribution of ages changes as the individual grows older. We found that human cardiomyocytes in healthy hearts indeed renew throughout life, with a declining turnover not exceeding 1% per year in adult life, and that the cell number is established already at birth. Endothelial and mesenchymal cardiac cells are more dynamic, both in terms of changes in cell number and baseline turnover (Paper II and IV). Preliminary results indicate that ischemic heart disease and dilated cardiomyopathy can increase the renewal rate to 2.7% per year; however it is likely that individual turnover estimates differ from this, which may reflect the differences in disease etiology and patient specific manifestation (Paper I). In order to reach these conclusions we developed a method to isolate cardiomyocyte nuclei, based on the molecular markers, PCM-1, cTroponin T, and cTroponin I (Paper III). This work shows that adult cardiomyocytes in healthy and diseased hearts have a measurable regenerative capacity, suggesting that it can be exploited for developing new therapeutic strategies to treat heart disease.