Youth is wasted on the young

Amphibians and zebrafish are able to regenerate lost myocardial tissue without loss of cardiac function; whereas mammals, in response to myocardial injury, develop scar and lose cardiac function. This dichotomy of response has been thought to be due to the fact that adult mammalian cardiac myocytes are multinucleated and have limited proliferative capacity. Neonatal mammalian cardiac myocytes do have a limited capacity to proliferate. What has been unknown is whether this limited proliferative capacity is associated with the ability to regenerate myocardial tissue soon after birth. Recently, it has been demonstrated that 1-day-old neonatal mice do have the ability to regenerate resected cardiac tissue, and that the capacity to regenerate cardiac tissue is lost by 7 days after birth. The present commentary reviews these results and attempts to offer perspective as to how these important findings relate to current and future strategies to prevent and treat cardiac dysfunction in clinical populations.

Following acute myocardial infarction, the human heart can lose over a billion cardiac myocytes. Th e injured tissue undergoes fi brosis, leading to signifi cant loss of contractile function, adverse left ventricular remodeling and ultimately chronic heart failure. Adult mammalian cardiac myocytes are multinucleated and it has been well documented that only a limited number of cardiac myocytes enter the cell cycle following myocardial repair [1]. Scientists at the bench have known for decades that cardiac myocytes isolated from adult mammalian myocardium do not enter the cell cycle and actively divide, whereas cardiac myocytes from neonatal myocardium do have a limited capacity to divide in culture. Th e limited proliferative capacity of adult cardiac myocytes correlates with the limited capacity of the adult myocardium to regenerate itself following acute myocardial infarction, and is in distinct contrast to the regenerative capacity of the myocardium in lower life forms, including zebrafi sh [2].
Th e recent publication by Porrello and colleagues sought to answer the question of whether the neonatal mammalian heart has the capacity for regeneration that is lost with aging [3]. To answer this question they resected the apex of the hearts of 1-day-old neonatal mice and found that the myocardium does regenerate. Th e regenerative process is accompanied by proliferation of cardiac myocytes that peaked at 7 days after resection. By 21 days after resection the apex of experimental animals was indistinguishable from that of sham animals, without any evidence of signifi cant scar. Furthermore, cardiac function and chamber dimensions were similarly un changed between experimental and sham-treated animals. In distinct contrast, apical resection in 7-day-old mice did not lead to cardiac myocyte proliferation or regenera tion of the lost apical tissue. Rather, the apex in the 7-day-old mice was markedly fi brotic, suggesting that the regenerative capacity of neonatal myocardium is lost within the fi rst week of life.
Th e ultimate issue is identifying the mechanism(s) behind myocardial regeneration in 1-day-old mice that is lost with aging, and whether this mechanism(s) can be re-established to achieve clinically meaningful regeneration in patients with left ventricular dysfunction. Figure 1 schematizes multiple potential mechanisms associated with myo cardial repair that could be, and arguably need to be, investigated.
Since the seminal work of Orlic and colleagues [4,5], the fi eld of cardiac regeneration has demonstrated the potential to induce cardiac repair using adult stem cells; however, it is unlikely that a signifi cant mechanism of the observed benefi t is associated with myocardial regeneration. Multiple stem cell populations have been studied and have demonstrated benefi t with multiple adult stem cell populations in preclinical studies [6,7] and in clinical populations [8][9][10][11][12]. Furthermore, the elucidation of relevant mechanisms associated with myocardial repair [13,14] has led to novel clinical trials that focus on inducing endogenous repair in the absence of stem cell delivery (Clinicaltrials.gov: CXCL12, NCT01082094, Th ymosinβ4 and NCT01311518).

Abstract
Amphibians and zebrafi sh are able to regenerate lost myocardial tissue without loss of cardiac function; whereas mammals, in response to myocardial injury, develop scar and lose cardiac function. This dichotomy of response has been thought to be due to the fact that adult mammalian cardiac myocytes are multinucleated and have limited proliferative capacity. Neonatal mammalian cardiac myocytes do have a limited capacity to proliferate. What has been unknown is whether this limited proliferative capacity is associated with the ability to regenerate myocardial tissue soon after birth. Recently, it has been demonstrated that 1-day-old neonatal mice do have the ability to regenerate resected cardiac tissue, and that the capacity to regenerate cardiac tissue is lost by 7 days after birth. The present commentary reviews these results and attempts to off er perspective as to how these important fi ndings relate to current and future strategies to prevent and treat cardiac dysfunction in clinical populations. In the study by Porrello and colleagues, the authors attempted to determine whether the cardiac myocytes in the regenerated apical tissue were derived from endogenous cardiac myocytes or a source of progenitor cells [3]. To address this question they cross the αMHC-MerCreMer mouse with the Rosa26-lacZ reporter mouse. Th e mice were treated with a single dose of tamoxifen at birth. Th e dosing of tamoxifen led to chimeric cardiac myocytes with a specifi c percentage being lacZ-positive. If the apex was regenerated from endogenous cardiac myocytes, then the regenerated tissue should have the same percen tage of lacZ-positive cardiac myocytes; whereas if the tissue was regenerated from a progenitor pool, then the apex would have a higher percentage of lacZ-negative cardiac myocytes since the tamoxifen would not have activated the αMHC-MerCreMer promoter in these cells. Th e data nicely demonstrate that the regenerated apex had the same proportion of lacZ-positive cardiac myocytes as the endo ge nous myocardium [3], suggesting that the regenerated tissue was derived from endogenous cardiac myocytes. While this may be accurate, what is not taken into account is that the αMHC-MerCreMer promoter is activated in cardiac stem cells. Th ese mice therefore probably have a chimera of lacZ-positive and lacZnegative cardiac stem cells from which the cardiac myocytes in the regenerated apex could have been derived.
Regardless, the fi ndings of the paper are relevant since there is little evidence that adult cardiac stem cells can regenerate cardiac myocytes [15].
Consistent with the observations by Porrello and colleagues with respect to myocardial regeneration, stem cell function and endogenous myocardial repair are lost with aging. We recently demonstrated that cardiac myocyte hypertrophy in response to pressure overload is age dependent. We further demonstrated that aging leads to a decline in the generation of bone-marrow-derived cardiac stem cells, and that the eff ects of aging on cardiac myocyte hypertrophy could be reversed by trans plantation of young bone marrow into aged mice [16].
Th e loss of cardiac myocyte regeneration and repair with aging may help explain the rarity of cardiac tumors. Such observations suggest that dissecting the cardiac regenerative and reparative mechanisms lost with aging that have relevance to tumor suppression could yield important targets for future therapeutic approaches. One such example is our recent fi nding that downregulation of the tumor suppressor protein disabled-2 results in signi fi cantly improved stem-cell-based cardiac repair [17].
In summary, the study by Porrello and colleagues demonstrates that the complete regeneration of myocardial tissue is possible in mammals [3]. Th is observation is important because we now know that myocardial regeneration is a natural process in mammals; and if we can defi ne the associated mechanisms, and determine how these mechanisms are modulated by aging, new therapeutic strategies targeted at myocardial regeneration should be possible.