Stem Cells from Surgery Might Heal Damaged Hearts

Stem cells from surgery? Come off it. Well it’s true. For the first time, scientists have extracting stem cells from sections of vein removed for cardiac arterial bypass graft (CABG) surgery. These stem cells can even stimulate new blood vessels to grow and these can potentially help repair damaged heart muscle after a heart attack. This research was conducted by Paolo Madeddu (Professor of Experimental Cardiovascular Medicine) and co-workers at the Bristol Heart Institute (BHI) at the University of Bristol. It was recently published in the journal Circulation.
Some 20,000 people each year undergo CAGB, and this procedure takes a section of vein from the person’s leg and grafts it onto a diseased coronary artery to divert blood around a blocked or narrowed coronary artery. Surgeons normally extract a longer section of vein than is needed for the bypass surgery. This Bristol team successfully isolated stem cells from leftover veins that patients had agreed to donate.
When they used these stem cells in mice, they were able to stimulate the growth of new blood vessels into injured leg muscles. Madeddu and his team are now determining if the cells can help the heart to recover from a heart attack. Madeddu said: “This is the first time that anyone has been able to extract stem cells from sections of vein left over from heart bypass operations. These cells might make it possible for a person having a bypass to also receive a heart treatment using their body’s own stem cells. We can also multiply these cells in the lab to make millions more stem cells, which could potentially be stored in a bank and used to treat thousands of patients.”
Professor Peter Weissberg, Medical Director of the BHF, said: “Repairing a damaged heart is the holy grail for heart patients. The discovery that cells taken from patients’ own blood vessels may be able to stimulate new blood vessels to grow in damaged tissues is a very encouraging and important advance. It brings the possibility of ‘cell therapy’ for damaged hearts one step closer and, importantly, if the chemical messages produced by the cells can be identified, it is possible that drugs could be developed to achieve the same end.”

Pancreatic cells can convert into insulin-secreting beta cells

Diabetes mellitus is caused by the either the inability of the pancreas to produce sufficient quantities of insulin to service the needs of the body (type 1), or the tissue to not sufficiently respond to insulin (type 2).

Insulin is made by specific cells in the pancreas called “beta cells.” These beta cells are isolated from the “exocrine” portion of the pancreas that make all the digestive enzymes that are secreted into the small intestine to digest the complex molecules in our food. These isolated tissues are islands of cells in a sea of exocrine tissue and are literally called “pancreatic islets” or “isles of Langerhans.”

The pancreatic islets contain several different cell types, but the main cells are alpha cells, which make the hormone glucagon and beta cells which make the hormone insulin. Insulin is made in response to increased glucose levels in the blood and glucagon is made in response to low glucose levels in the blood. Type 1 diabetes mellitus often results when the immune system attacks and destroys the beta cells, and this greatly reduces the amount of insulin made in response to high glucose levels. This causes chronically high blood glucose levels, which is the hallmark of diabetes mellitus. The Holy Grail of diabetes research is to regenerate beta cells that were lost in diabetics.

Embryonic stem cells (ESCs) can differentiate into beta cells. When removed from feeder cells, mouse and human ESC cultures form “embryoid bodies” or EBs. EBs are clusters of ESCs that contain cells that have differentiated into a wide variety of cells types. EBs contain beating heart muscle cells, nerve- and gland-like cells, and also, pancreatic beta cells (see S Assady, et al., Diabetes 50 (2001): 1691–1697; and ML Khoo, et al., Biol Reprod 73 (2005): 1147–1156). There are several strategies for increasing the efficiency of beta-cell production from ESC cultures (H Segev, et al., Stem Cells 22 (2004): 265–274; N Lumelsky, et al., Science 292, (2001): 1389–1394; Y Hori, et al., Proc Natl Acad Sci USA 99 (2004): 16105–16110; H Baharvand, et al., Dev Growth Differ 48 (2006): 323–332), but some of these protocols do not work all that well and others do not work when tried by other people (J Rajagopal, et al., Science 299, (2003): 363; M Hansson, et al., Diabetes 53 (2004): 2603–2609). However, the PAX4 gene, if expressed at high levels, can increase the efficiency of beta-cell differentiation of ESCs (CG Liew, et al., PLoS One 12, no. 3 (2008): e1783).  Other cells can also differentiate into beta cells that are not embryonic stem cells (K Juhl, et al., Current Opinion in Organ Transplantation 15, no 1 (2010):79-85).  There is reason for optimism.

Now a new report has shown that alpha cells in the pancreas, which, remember, do not produce insulin, can convert into insulin-producing beta cells. This is a potential protocol for regenerating beta cells as a cure for type 1 diabetes. These findings come from a study at the University of Geneva, co-funded by the Juvenile Diabetes Research Foundation.

Pedro L Herrera, the lead researcher of this group, showed that beta cells will spontaneously regenerate after near-total beta cell destruction in mice and the majority of the regenerated beta cells are derived from alpha cells that had been reprogrammed, or converted, into beta cells. When they used a unique model of mouse diabetes in which nearly all of the beta cells are rapidly destroyed, if the mice were maintained on insulin therapy, beta cells were slowly and spontaneously restored, eventually eliminating the need for insulin replacement.

Herrera’s results are the first to show that beta cell reprogramming can occur spontaneously, without genetic alterations. Previous efforts to reprogram non-beta cells into beta cells relied on genetic manipulations – processes that cannot be easily translated into therapies.

The critical factor in sparking the alpha-to-beta-cell reprogramming was removing (or ablating) nearly all the original insulin-producing cells in the mice. In mice where the loss of beta cells was more modest, the researchers either found no evidence of beta cell regeneration was observed (when only half the cells were destroyed) or less alpha cell reprogramming (when less than 95% of cells were destroyed) occurred. Herrera said, “The amount of beta-cell destruction thus appears to determine whether regeneration occurs. Moreover, it influences the degree of cell plasticity and regenerative resources of the pancreas in adult organisms.”

In addition to regenerating or replacing insulin producing cells, a cure for type 1 diabetes will also require stopping the autoimmune attack that causes diabetes, and reestablishing excellent glucose control.

Induced Embryonic Stem have a silenced region of the genome

Induced pluripotent stem cells (iPSCs) are similar to embryonic stem cells (ESCs), which are made from embryos, but these two types of stem cells have some distinct differences. iPSCs for instance, are somewhat slow to grow than their ESC counterparts. They also have a capacity to form nerve cells (neurons), but they also do so somewhat inefficiently.

Now a group has identified particular genetic differences between iPSCs and ESCs and this might determine why these two types of stem cells show different growth characteristics. This study examined mouse iPSCs and ESCs, and if confirmed in humans, such a finding might help clinicians to select only the best stem cells for therapeutic applications and disease modeling.

iPSCs are created by reprogramming adult cells. They resemble ESCs in that both cell types are pluripotent, which is to say that they can form any tissue in the body.

A team at Massachusetts General Hospital, led by Konrad Hochedlinger, has now made iPSCs and ESCs with identical DNA, and the iPSCs incorporated into chimeric mice with a much poorer efficiency than ESCs. Because such incorporation experiments are a standard test of pluripotency. They added the iPSCs and ESCs into embryos from mice of that have different colored fur. Once each mouse matures, the color of its fur coat reveals how well the stem cells contributed to forming its skin. ESCs contributed much more robustly to the fur of the mice than did iPSCs.

Secondly, when these scientists compared genome-wide gene expression patterns in ESCs and iPSCs, they discovered that a small stretch of DNA on the long arm of chromosome 12 had very different levels of gene activity. In this region, two genes and a slew of tiny regulatory sequences called microRNAs were consistently activated in the ESCs, but silenced in iPSCs regardless of whether the reprogrammed cells came originally from skin, brain, blood or other tissue. The function of the key genes in this region are unknown, but this region is usually silenced in mouse sperm cells and activated in other types of cell, so reprogramming might somehow mimic the silencing process.

This discovery implies that human iPSCs carry similarly silenced sequences that make them less effective than ES cells.

Although iPSCs in these experiments did not meet the strictest criteria of stemness, since they did not introduce significant coloring into the fur of chimeric mice, but they may still have been able to form many types of tissue, something the researchers did not explicitly test.

Although findings in mice don’t always apply to humans, if a similar gene signatures are found in human iPSCs, it could help researchers to identify which iPSCs to avoid using, and which stand the best chance of producing a desired tissue. Hochedlinger’s team has therefore begun to look at human ES and iPSCs in search of similar gene-activity patterns to those they found in mice.