Cell proliferation in the growing human heart: MIB-1 immunostaining in preterm and term infants at autopsy

Huttenbach, Yve; Ostrowski, Mary L.; Thaller, David J; Kim, Han-Seob

doi:10.1016/s1054-8807(01)00065-5

Cited by 44 publications

(36 citation statements)

References 18 publications

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“…This is shown by an immunohistochemical study in human hearts by Huttenbach et al (26), which reports a comparatively high rate of proliferation from 12 to 28 wk of gestation, with a significant decrease in proliferation after 28 wk of gestation. This finding is in line with stereological studies in fetal and early postnatal human hearts by Mayhew et al (27), which suggest that proliferation ceases approximately 2-3 wk after birth.…”

Section: Discussionmentioning

confidence: 89%

“…This model has been proven useful for neurologic studies because, with regard to brain development, a 7-d-old rat is roughly equivalent to a full-term human infant and, consequently, term rat pups may correspond well to premature infants (37). Furthermore, at d 1-3 after birth, the rat myocardium still shows substantial hyperplasia (28), similar to the preterm human myocardium (26,27). Thus, with respect to the transition from myocyte hyperplasia to hypertrophy, the term rat pub appears to be a good model for the preterm human infant.…”

Section: Discussionmentioning

confidence: 99%

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Neonatal Glucocorticosteroid Treatment Causes Systolic Dysfunction and Compensatory Dilatation in Early Life: Studies in 4-Week-Old Prepubertal Rats

et al. 2005

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Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n ϭ 12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 g/g) of life. Control pups (n ϭ 10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasonetreated rats had a reduced ventricular weight (270 Ϯ 40 versus 371 Ϯ 23 mg, p Ͻ 0.001) and reduced systolic function (endsystolic elastance: 1.24 Ϯ 0.43 versus 2.50 Ϯ 1.39 mm Hg/L, p ϭ 0.028). Cardiac output was maintained and end-diastolic volume was increased (84 Ϯ 23 versus 59 Ϯ 19 L, p ϭ 0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention. Glucocorticosteroids, in particular DEX, are widely used to treat or prevent chronic lung disease in preterm infants (1). Besides their antiinflammatory action, glucocorticosteroids stimulate lung maturation and enhance surfactant production (2,3). Thus, glucocorticosteroid treatment improves pulmonary function and enables early weaning from the ventilator and, consequently, increased survival of extremely premature neonates (4).In the past two decades DEX therapy in preterm infants has gained wide acceptance. However, despite the short-term beneficial effects, concerns have been raised about long-lasting negative side effects of glucocorticosteroids (5-7). Several studies describe neurodevelopmental impairments in infants treated with glucocorticosteroids in the neonatal period (8 -10).With regard to the cardiovascular system, hypertension and reversible myocardial hypertrophy have been reported (11-13), but possible long-term effects became apparent only recently. De Vries et al. (14) showed that rats treated with DEX in the neonatal period had decreased heart weights, as well as hypertrophy and signs of early degeneration of cardiomyocytes in 85-23, revised 1996).Pregnant Wistar rats (270 -300 g) we...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Neonatal Glucocorticosteroid Treatment Causes Systolic Dysfunction and Compensatory Dilatation in Early Life: Studies in 4-Week-Old Prepubertal Rats

et al. 2005

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“…Similar to the rat, in the preterm infant a high proportion of cardiomyocytes are immature and still exhibit a proliferative phenotype at the time of birth (Huttenbach et al, 2001). Our results suggest that the complement of cardiomyocytes may not be compromised by preterm birth per se but will be directly influenced by postnatal growth of the heart during the time when the cardiomyocytes are still capable of division.…”

Section: Discussionmentioning

confidence: 99%

Effect of Maternal Protein Restriction During Pregnancy and Lactation on the Number of Cardiomyocytes in the Postproliferative Weanling Rat Heart

Lim

Zimanyi

Black

2010

The Anatomical Record

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Maternal protein restriction leads to a reduction in the number of cardiomyocytes in the rat heart at birth. However, in rats, cardiomyocytes continue to proliferate until about 2 weeks after birth. Hence, this study aimed to examine the effect of maternal protein restriction, on the number of cardiomyocytes in the young rat heart at a time point when the cardiomyocytes have ceased proliferating and are terminally differentiated. Female Wistar Kyoto rats were fed either a normal protein diet (NPD; 20% casein) or a low protein diet (LPD; 8.7% casein) during pregnancy and lactation. Offspring (seven males and seven females per group) were perfusion fixed at 4 weeks of age. Heart volume and total cardiomyocyte number were determined using stereological techniques. At 4 weeks of age, body weights in both male and female LPD offspring were significantly reduced compared with NPD controls whereas relative heart volumes were significantly increased in LPD offspring. Total number of cardiomyocytes was not significantly different between groups. In both groups, there was a significant linear correlation between cardiomyocyte number and heart volume. In conclusion, total cardiomyocyte number in the postproliferative rat heart does not appear to be affected by maternal protein restriction per se but is directly related to heart size. Anat Rec, 293:431-437, 2010. V V C 2010 Wiley-Liss, Inc.

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“…Attempts to create permanent lines of proliferating cells that retain the proper cardiomyocyte phenotype have met with limited success [2][3][4][5]. Although various mitogens have been purported to stimulate proliferation of cardiomyocytes in different model systems (see [6] and [1] for thorough reviews), the limited availability of human cardiomyocytes has restricted study to relatively few investigations in vivo [7][8][9] or in vitro [10][11][12][13], and such studies were dependent on the availability of human fetal tissue sources.…”

Section: Introductionmentioning

confidence: 99%

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

McDevitt¹,

Laflamme

Murry

2005

Journal of Molecular and Cellular Cardiology

168

125

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Cardiomyocytes from common experimental animals rapidly exit the cell cycle upon isolation, impeding studies of basic cell biology and applications such as myocardial repair. Here we examined proliferation of cardiomyocytes derived from human and mouse embryonic stem (ES) cells. While mouse ES cell-derived cardiomyocytes showed little proliferation, human cardiomyocytes were highly proliferative under serum-free conditions (15-25% BrdU+/ sarcomeric actin+). The cells exhibited only a small serum dose-response, and proliferation gradually slowed with increasing differentiation of the cells. Neither cell density nor different matrix attachment factors affected cardiomyocyte proliferation. Blockade of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt significantly reduced cardiomyocyte proliferation, whereas MEK inhibition had no effect. Antibody blocking of the insulin-like growth factor-1 (IGF-1) receptor significantly inhibited cardiomyocyte proliferation, while addition of IGF-1 or IGF-2 stimulated cardiomyocyte proliferation in a dose-dependent manner. Thus, cardiomyocytes derived from human ES cells proliferate extensively in vitro, and their proliferation appears to be mediated primarily via the PI 3-kinase/Akt signaling pathway, using the IGF-1 receptor as one upstream activator. This system should permit identification of regulatory pathways for human cardiomyocyte proliferation and may facilitate expansion of cardiomyocytes from human ES cells for therapeutic purposes.

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Cell proliferation in the growing human heart: MIB-1 immunostaining in preterm and term infants at autopsy

Cited by 44 publications

References 18 publications

Neonatal Glucocorticosteroid Treatment Causes Systolic Dysfunction and Compensatory Dilatation in Early Life: Studies in 4-Week-Old Prepubertal Rats

Neonatal Glucocorticosteroid Treatment Causes Systolic Dysfunction and Compensatory Dilatation in Early Life: Studies in 4-Week-Old Prepubertal Rats

Effect of Maternal Protein Restriction During Pregnancy and Lactation on the Number of Cardiomyocytes in the Postproliferative Weanling Rat Heart

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

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