Change of Heart: Fickle Cells Cause Cardiac Scarring

The discovery of some unusual behavior in adult heart cells after injury may point to treatment for fibrosis, the slow organ scarring that eventually causes heart failure.

The cells are endothelial cells, which normally provide an inner lining for blood vessels. According to new work from the lab of Raghu Kalluri, HMS associate professor of medicine at Beth Israel Deaconess Medical Center, a heart attack or other insult can turn the cells into fibroblasts, the creators of scar tissue.

Courtesy Raghu Kalluri

Raghu Kalluri (right) relaxes with mentor Elizabeth Hay, who recently passed away.

Scarring fibroblasts are not found in the normal heart in large numbers, and where they come from during fibrosis has been a mystery.

“Our results indicate that injury sets up an environment of cytokines and other factors that promote the change of endothelial cells into fibroblasts,” said Kalluri. The transition is one that occurs during embryonic heart development, but it has not been seen before in adult tissues.

The investigators go on to show that the same cytokine that induces the embryonic switch, TGF-beta1, contributes to heart fibrosis in adult mice. Likewise, a known inhibitor of embryonic heart development, bone morphogenic protein-7, inhibited the switch, reduced fibrosis, and improved heart function in the animals modeling a heart attack or rejection of a transplanted heart. 

The same researchers have documented a similar transition in other organs prone to fibrosis, including the lung, liver, and kidney. This raises the possibility that targeting the TGF/BMP pathway could lead to a broad-based treatment for fibrosis that occurs in many organs and diseases, Kalluri said.

According to Kalluri, much of the mechanistic credit for this new understanding of fibrosis belongs to the late Elizabeth Hay, the Louise Foote Pfeiffer professor emerita of embryology in the Department of Cell Biology, who passed away in August (see obituary). Hay discovered what is called the epithelial-to-mesenchymal transformation (EMT) in embryonic development. (The mesenchyme gives rise to fibroblasts.) Her work started an entire field in cell biology devoted to studying the EMT.

Kalluri remembers Hay as a pioneer in studies of the extracellular matrix and EMT, an ardent supporter of his work, and a dear colleague. “We were friends and neighbors. It was very endearing how she constantly would call and encourage us to pursue this area of research. I will miss her collegiality,” he said. “She pushed the idea that the EMT was involved not only in development but also in disease, and I want to acknowledge her role in this work.”

The study appeared in the August Nature Medicine.

—Pat McCaffrey

Eye Clock Keeps Local Time

The eye is its own master when it comes to keeping a circadian rhythm, according to a new study from the lab of Charles Weitz, the Robert Henry Pfeiffer professor of neurobiology at HMS. The work, published in the Aug. 24 Cell, shows that in mice, the eye clock ticks independently of the master circadian clock in the brain and regulates the expression of thousands of genes. Ultimately, this translates to periodic changes in the way visual information is relayed in the inner retina. The result is a level of local control that lets animals anticipate and prepare for the daily transition from dark to light and vice versa. 

“The role of circadian clocks is to coordinate complicated systems in anticipation of regular environmental changes, like light and dark,” said Weitz. “We suspected that the retina uses its own time-keeping mechanism to locally control tissue-specific functions, and that’s what we found.”

In higher animals, a master clock in the brain controls sleeping, waking, eating, and other activities over a 24-hour cycle through the rhythmic production and destruction of clock proteins. Recently, researchers discovered that these proteins also cycle in many cells outside the brain, including the eye, heart, liver, and other peripheral organs. The physiological role of these clocks and the extent to which they are slaves of the master clock or operate independently was mostly unknown.

To find out what genes and pathways are regulated by the endogenous retinal clock, the investigators analyzed gene expression patterns in mouse eyes over a three-day span. Using large-scale microarray chips, they found that hundreds of genes were expressed rhythmically in the eye, even when the mice were kept in total darkness.

In mice that had the master clock cells in the brain destroyed, the retinal clock continued to run and generate daily variations in electrical activity in response to light. This indicated that the retinal clock operates separately from the brain’s main circadian cells. 

The researchers then disabled just the retinal clock, using an eye-specific genetic knockout of one key clock protein. The result was to abolish the daily periodicity in gene expression. The knockout also affected eye function, disrupting the normal daily oscillation in electrical signals generated by the retina in anticipation of daybreak or nightfall.

Disrupting the retinal clock unexpectedly disturbed the expression of many genes that are normally regulated by light itself, giving the first clue that clock genes can regulate the response of broad swaths of the genome to environmental changes in a rhythmic way.

“Systems that can anticipate regular changes in the environment presumably have a big advantage over systems that passively respond to changes as they occur,” Weitz explained. “Our results indicate that the retina has taken the clock mechanism and is using it to take broad control of gene expression and functions.” The ability to make tissue-specific clock knockouts will allow the researchers to ask whether the same is true for other peripheral clocks. 

—Pat McCaffrey

Underinsured Children Lack Access to Recommended Vaccines

Due to limited federal and state funding for vaccines, underinsured children in the United States are increasingly at risk for not getting needed immunizations, according to a study in the Aug. 8 Journal of the American Medical Association.

Led by Grace Lee, HMS assistant professor of ambulatory care and prevention at Harvard Pilgrim Health Care and of pediatrics at Children’s Hospital Boston, the study found that many underinsured children fail to receive government-purchased vaccines in either a private doctor’s office or public health clinic.

“Childhood immunization is ranked as one of the most important preventive health services we can offer,” said Lee. “Due to the increased cost of recently recommended vaccines and the lack of available funding, many states have been forced to adopt more restrictive policies for the provision of publicly purchased vaccines. Underinsured children, who used to be able to rely on public health clinics as a safety net in the past, are now at risk of not getting immunized for serious childhood illnesses.”

Childhood vaccines are funded by a patchwork of public and private sources. While some private health insurance plans cover the recommended vaccines, an increasing number require patients to pay for some of them. Due to a decline in public funding and increases in the number and cost of vaccines, many underinsured children and their families are faced with the dilemma of going without immunizations or finding a federally qualified health center or rural health center (often a great distance away) that offers government-purchased vaccines free of charge. In contrast, children who are either uninsured or publicly insured through Medicaid can receive the vaccines through the federal Vaccines for Children Program.

In one part of the two-phase study, the researchers interviewed immunization program managers from 48 states. They found that in the private sector, 30 states were unable to provide meningococcal conjugate vaccine to underinsured children, and 24 states could not provide them with pneumococcal conjugate vaccine. In the public sector, those numbers were 17 and 8, respectively. This means, for example, that approximately 2.3 million children could not receive publicly purchased meningococcal conjugate vaccine in the private sector, and 1.2 million could not receive the vaccine even if they were referred to public sector clinics.

“Studies suggest that many private clinicians refer underinsured children to public health clinics for vaccination,” said Tracy Lieu, senior author on the study and an HMS professor in the Department of Ambulatory Care and Prevention. “Unfortunately, a growing number of states no longer provide the most expensive vaccines to these children. The problem may become worse since the trend in private health insurance is to shift to higher deductible plans and, in many cases, vaccines may not be covered unless the deductible is reached. This could put children from economically vulnerable families at risk of not getting vaccinated.”

Lee warns that the situation is creating significant ethical dilemmas for public health clinicians who are being forced to turn away underinsured children or ask families to pay for needed vaccinations.

—Ann Plasso

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