Can a Heart Repair Itself Via Stem Cells

Can a heart repair itself via their own stem cells and do hearts have meaningful populations of stem cells?

Science evolves

Sometimes what we scientists all know to be true turns out later on to be wrong and there are clear instances of this in the stem cell field.

For example for decades the dogma was that the adult mammalian brain did not have stem cells, but now most researchers believe that the adult brain does have stem cells, although for humans this is still being debated.

What we perceive as factual can change over time.

Yamanaka disproved the entrenched notion that differentiated cells were permanently locked into that differentiated state with his revolutionary findings on induced pluripotent stem cells. The new reality, which seemed revolutionary in some ways in 2006-2007, now is established fact.

So what about the idea of the human heart have resident populations of stem cells that can fix problems, perhaps as severe as damage from heart attacks? One of the first stem cell talks I ever saw way back around IPS cells were discovered was by a guy who assumed the factual answer to this question was “Yes!”

What about now in 2020? I have an ongoing Twitter poll on this question as of Nov. 5, 2020 so check it out below.

Can damaged human hearts meaningfully repair themselves via their own endogenous populations of stem cells? #stemcells #cardiology #heartdisease

— Paul Knoepfler (@pknoepfler) November 5, 2020

Can damaged hearts repair themselves via stem cells?

Today the cardiac regenerative field finds itself at an interesting crossroads.

A few say “yes” there are cardiac stem cells and that they can mediate repair. However, most heart researchers that I’ve talked to in recent years feel just as strongly that there are no such cells. Some also have added that even if there are at least a handful of such cells or they arise due to damage, they can’t do anything meaningful about serious heart damage.

I asked cardiac stem cell expert, Deepak Srivastava for his thoughts on this in a previous post and found his answer compelling. Because that was a fairly long time ago, I got an update to the same kind of question just now from two leading cardiac regenerative medicine and stem cell researchers.

Associate Professor of Medicine and Director of Cardiovascular Regenerative Medicine at Mt. Sinai, Hina Chaudhry had this to say:

“One thing is certain: As both a clinical cardiologist who has cared for patients with heart attacks and a stem cell biologist, I can tell you that no scientific data supports an endogenous stem cell population in the adult heart and that no adult with a transmural myocardial infarction ever loses the resulting scar throughout their lifetime.”

Professor Chuck Murry of the UW sent this:

“Our current best evidence suggests that there are no stem cells in the adult heart that can give rise to new cardiomyocytes.  This has been studied intensively—from the bottom up, by tracing candidate stem cells and following their differentiated progeny, and from the top down by marking pre-existing cardiomyocytes and looking for their dilution as unmarked stem cells enter the pool.  Both have shown the same thing: if this happens at all, its frequency is on the order of 10e-4 per year, which by any measure is next to nothing.  There is slow turnover of cardiomyocytes in the adult mammalian heart, at ~1% per year, and this can be accounted for entirely by replication of pre-existing cardiomyocytes.  One has to wonder, why has Nature done this?  Why would such a vital organ have no stem cells for replenishment, along with such a low rate of endogenous replication?”

I believe that Drs. Murry and Chaudhry are right. Chuck’s last question there is one for long discussions and is similar to discussions I’ve had about the few stem cells/potential for endogenous repair in the adult human brain.

Steady stream of papers on heart stem cells

Still, you can find a diversity of papers now in 2020 in PubMed with “Heart Regeneration” or “Cardiac Regeneration” or “Cardiac stem cells” in their titles. However, many of the papers relate to stem cell infusions rather than invoking endogenous resident cells.

If not in humans, what about other mammals? There are glimpses of interesting possible stem cell activity in the mammalian heart, even if not in humans

A November 2014 Cell Stem Cell paper from the lab of Juan Carlos Izpisua Belmonte, entitled “In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration”, argues for endogenous mammalian heart regeneration in part via dedifferentiation of cells into stem-like cells. This raises the interesting notion that while the mammalian heart does not normally have many (or any?) resident stem cells, damage can change some other cells into stem cell-like cells.

Heart Repair: Past controversy

One of the biggest advocates of endogenous cardiac stem cells and repair, Piero Anversa formerly of Harvard and Brigham and Women’s Hospital, has become one of the most controversial as well. His papers have come under fire and some have been retracted. Anversa was the subject of a Harvard investigation and was suing Harvard for how it has conducted the investigation and other matters related to his work.

In my view, his situation has raised even more skepticism about the idea of endogenous heart stem cells in people.

Looking ahead, including stem cell transplants

Even if the endogenous stem cell-like activity in the heart is absent or not enough to mediate clinically significant repair in humans, by deciphering the molecular basis of this kind of activity in other animals could the field still open the door to powerful new treatments for heart disease? For instance, if some adult mammalian hearts naturally replace 1 in 200 cells per year, perhaps cardiac researchers can find a way to boost that by an order of magnitude with a drug and have a meaningful impact for human patients.

Or if dedifferentiation of non-stem cells in the heart into stem cell-like cells can be induced by damage, could a drug therapy trigger that same effect even if damage occurred long ago or in the context of relatively minor damage?

Many researchers are focusing more on using injections of stem cells into the heart to repair damage. The types of stem cells being used for research attempts at heart repair are very diverse, including both placental cells and indirect use of IPS cells in Japan via a recently approved trial there.

Even the area of stem cell transplants into the heart generates its share of debate and we’ll have to see in the long run how the clinical trial data turn out. I hope there can be positive impact in the future given the overwhelming number of people with heart damage.