Tuesday, November 26, 2013

Damaged hearts may be healed by their own stem cells

Thanks to stem cells, each of us develops from a single-celled embryo into a fetus with hundreds of different cell types. Stem cells multiply and specialize until they become heart muscle, bone, nerves, etc. Tissues like skin keep pools of stem cells on hand into adulthood, activating them as needed to replace worn out cells in a constant turnover.

But not the heart. Cardiologists believed for a long time that you get one set of heart cells for life. If you lost a bunch in the wake of heart attack, you had to live with whatever was left. In recent years, however, researches have revised that view. There is cell turnover in the heart, albeit as a much slower pace than that seen in other tissues.

The existence of such replenishing mechanisms suggested that it may be possible to coax them into action to regenerate heart muscle damaged by disease. Results of early human trials have been positive, although there is still work to do before such treatments become part of clinical practice.

It may be no surprise then stem cell-based therapies were a focus of the recently held UAB Comprehensive Cardiovascular Center’s Annual Symposium. We sat down with Sumant Prabhu, M.D., director of the center and symposium organizer to talk about the promise of regenerative medicine.

1:32 Dr. Prabhu said he organized the symposium with this theme at this time because his team wanted to focus on the next wave of science and therapeutics in cardiology. He believes that stem cell-based, genetic and tissue regeneration therapies will dominate the field in the coming years, just as drugs and devices did in during eras past. The symposium was designed to foster new collaborations in these areas among leading researchers.

3:19 Several symposium presentations were dedicated to stem cells that are present in the heart, and on attempts to manipulate them such that the become needed replacement cells in damaged hearts. Over the last ten years, clinical trials have examined the value of stem cells taken from the bone marrow or blood to repair damaged hearts, but a more recent thrust is the use of stem cells in the heart itself.

4:37 Joshua Hare, M.D., from the University of Miami, described in his presentation the use of mesenchymal stem cells, which can become bone, cartilage or fat cells, and how they showed "incredible promise" in clinical trials.  The studies looked at whether they could repair heart tissue after heart attack, and heart failure, the loss of pumping efficiency, seen in the wake of heart attacks. While these studies are promising, the field still has a long way to go before stem cell treatments become part of standard medical practice.

5:35 Harvard's Piero Anversa, M.D., delivered the keynote lecture for the symposium on the topic of stem cells in the heart, their discovery, their use in animal studies to repair hearts damaged by heart attack. In particular he described strong, early results in the Phase I human Scipio trial. In this trial, researchers removed stem cells from the hearts of patients as they underwent coronary bypass surgery. The research team then reinfused each patient's stem cells into their hearts after the surgery, where they proved to be safe, to improve pumping function and to lessen the amount of dead tissue in the heart.

6:39 Stem cell therapies target tissue that forms scar when damaged by a heart attack. Scar tissue is made of structural cells instead of functional muscle cells, and scars interfere with the hearts ability to pump blood (heart failure). Dr. Prabhu said there are often pockets of live tissue within the scarred area.  The hope is that added stem cells will receive signals from the surviving areas that turn them into the kind of cells that either improve the remaining tissue or build new tissue.

9:04 It was actually the dawn the nuclear era that made possible the discovery of the slow stem-cell led turnover of heart muscle. Heart cells exposed to low level of radiation from power plants, for instance, could the be carbon dated to show cell turnover. There is not much turnover, but over a lifetime it makes hearts more durable. After a heart attack, the process of stem-cell based tissue replacement seems to kick up a notch, said Dr. Prabhu, but obviously not enough to counter the massive damage caused by a heart attack. What if researchers could temporarily pump up this natural response? Would more the presence of more stem cells mean more rebuilding of tissues in of damaged areas?

10:28 Whether injected stem cells themselves bring about cardiac repair or whether they trigger some chain reaction that brings about repair is a matter of debate. How much heart muscle for instance that grows back in damaged hearts after stem cells are infused has varied considerably from study to study. What has been shown in animal studies is that stem-cell driven regeneration can be manipulated to improve cardiac function. Human studies are seeking to confirm that now.

Thursday, November 7, 2013

Nobel Prize focused on life-giving cellular cargo delivery system

A Nobel Prize was recently awarded to three researchers who discovered bubbles within bubbles that have tentacles. Award winners James Rothman, Randy Schekman and Thomas S├╝dhof were pioneers in the study of vesicles, which are like bubbles inside human cells whose outer layers are made of the same stuff that separates cell insides from the outside world. Because the bubbles’ insides are kept separate from the rest of the cell’s interior, they can store, organize and deliver highly reactive biochemicals and proteins, releasing them only when and where they’re needed.
Electron microscope images of vesicles near Golgi complex in a cell.

Furthermore, the outer membranes of vesicles can fuse to outer cell membranes or to the membranes surrounding other cellular machines. This lets them take in contents from one compartment, move them to another walled-off area, and deposit them there. It also lets a cell start manufacturing a hormone or an antibody in one spot, truck it somewhere else for finishing, move it to the cell's surface, and secrete it to do a job elsewhere in the body.

To ensure that it dumps its contents into the right compartment, each vesicle has tentacles,” squiggly proteins that taste” the surface of other vesicles to make sure they have reached the right destination. Without vesicle formation and fusion, cells could neither live nor signal to each other as part of complex tissues. Vesicles are so central to cellular function that they are most likely involved in almost every disease when things go wrong, although we don’t yet know their role.

For his share of the prize, Dr. Rothman, a professor at Yale, discovered a protein complex that lets vesicles fuse with membranes to deliver their molecular cargo. He has a UAB connection in his former student, Dr. Elizabeth Sztul, Ph.D., professor in the UAB Department of Cell, Developmental and Integrative Biology and a vesicle expert in her own right. Dr. Sztul said she was “thrilled” to see vesicle research be recognized in the form of a Nobel Prize, and we thought to ask her why her field deserves notice.

Show notes from the podcast

1:56  A Nobel Prize win for vesicle research underscores just how vital basic scientific research is, along with the fundamental importance of vesicles in human life, said Dr. Sztul. Cells are made of compartments, and the prize went to the three-scientist team for discovering how proteins and genes work together to move key substances from one compartment to another.

3:02  Vesicular traffic has implication for all of life. Genetic mistakes that occur in genes that control this delivery system mean that an embryo does not often survive, and if so, with severe disabilities. The Nobel Prize winners designed tests that identified the cogs (proteins) that make possible the machinery behind vesicle formation and transport.

4:15 Specifically, Dr. Rothman, a biochemist, identified the proteins required for vesicle transport and then re-created vesicle trafficking in a test tube. Dr. Schekman identified some of the genes that control vesicle transport, and that have done so throughout evolution. He works one-celled organisms like yeast that share vesicle pathways with human cells. Dr Sudhof, a neurobiologist, showed how vesicles deliver proteins, not just to the right place, but also with perfect timing, to make cellular life possible. Together, the pioneers outlined how a vesicle "knows" where to go and when to fuse.

5:47  Genetic mutations, random changes in that occur in genes as they constantly get copied, are usually fatal within a few days when they occur within the central machinery proteins of vesicle trafficking in a human embryo. Dr. Stzul describes one key vesicle protein type as snares, which help a vesicle grab on to the outside of another compartment they want to fuse with. Genetic defects in snares are fatal, but people are born with genetic changes in less essential machinery related to vesicles and survive.

6:22 For instance, proteins on the sides of vesicles that are nicknamed tethers or tentacles, touch and "sample" the outer membranes of surrounding vesicles to determine which they should target for fusion.  A mutation in one these protein tentacles causes a very serious, rare disease called congenital disorder of glycosylation. Tethers and snares represent two ways that any vesicle chooses a specific vesicle that it will deliver its cargo into.

8:40 There are many types of payloads delivered by vesicle in human cells. The immune system uses them to swallow invading bacteria, and then to deliver chemicals to that vesicle that destroy the bacteria.  Nerve cells use them to deliver signaling molecules to the next cell in line as a nerve message runs along a nerve pathway. After you eat a meal, cells in your pancreas packs digestive enzymes into vesicles and ship them off to the gut.

10:38 Vesicle delivery of proteins by cells is tightly regulated and very precise, Dr. Sztul said. Even small genetic errors in the genes that make the vesicle proteins can cause disease, including one called craniofacial disorder. These patients have bones that don't form properly because the structural protein collagen, which makes the lion's share of skin and bones, is not delivered properly by vesicles.

12:37  Dr. Sztul's lab is trying to figure out all of the steps needed to move all important proteins in the cell from where they are made, through every required vesicle stop along the way and to a final destination.  Each stop in this journey involves a web of interacting proteins, and Dr. Sztul would like to map all of these interactions precisely in time and space. She believe that this map, once complete, will reveal links between mutations in vesicle trafficking genes and many diseases, both common and rare. These patterns will emerge, she said, as more and more patients routinely get their DNA sequenced as part of personalized medicine.

15:00 With the map in place, researchers will have a basis for the design of treatments that compensate for problems with specific vesicle proteins. At least theoretically, every protein that regulates trafficking will become targets for drug design. In cancer for instance, vesicles may be used by tumors to deliver proteins that cause cancer cells to spread or that encourage the growth of blood vessels that feed tumors. Drugs might be designed to keep vesicles from making these harmful deliveries.

18:15 The field is working to invent imaging technologies that can track the movement and action in a living cell, not just of a couple of interacting proteins at a time, but that can watch perhaps 60 vesicle trafficking proteins at work during one stage of trafficking. Also on the horizon, an in-depth understanding of the interaction between vesicle trafficking and outer key cellular actions. How do hormones effect vesicle trafficking in cells that secrete hormones? How vesicles in immune cells become filled with antibodies when the body senses that it has been infected with a bacterium or a virus, or in response to a vaccine?