Man living in the Ecuadorian

Andes who suffers from

chronic mountain sickness

Photo courtesy of

UC San Diego Health

Findings from a study of people living at high altitude have implications for the treatment of red blood cell (RBC) disorders such as anemia and polycythemia, according to researchers.

To better understand why some people adapt well to life at high altitude while others don’t, the researchers studied RBCs derived from representatives of both groups who were living in the Andes Mountains.

The study revealed that high-altitude dwellers prone to chronic mountain sickness produce massive amounts of RBCs thanks to overproduction of the enzyme SENP1.

The researchers reported these findings in the Journal of Experimental Medicine.

“In addition to improving the health of millions of people around the world who live above 8000 feet, information on how Andeans have adapted—or not adapted—to high-altitude life might teach us how to speed up red blood cell production at lower altitudes, such as in anemia or when blood transfusions are needed rapidly,” said study author Gabriel Haddad, MD, of the University of California San Diego School of Medicine.

Dr Haddad and his colleagues noted that chronic mountain sickness affects approximately 20% of people who live at high altitudes, and a critical aspect of the condition is polycythemia.

Some extra RBCs can be beneficial in high-altitude, low-oxygen environments by helping to keep blood oxygenated. However, too many RBCs can increase the risk of heart attack and stroke, even in young adults.

For this study, the researchers collected skin cells from people living in the Andes Mountains—4 who were healthy and 5 who suffer from chronic mountain sickness—plus an additional 3 healthy people who live at sea level and served as controls.

To produce enough RBCs from each participant to study them in the lab, the researchers converted the skin cells into induced pluripotent stem cells (iPSCs).

Then, adding a cocktail of growth factors and other molecules, the team coaxed the iPSCs to differentiate into RBCs. Multiple samples were tested for each person, for a total of at least 24 iPSC lines.

The researchers exposed the RBCs to low-oxygen conditions that mimic high altitude—5% oxygen—for 3 weeks.

RBCs from healthy sea-level or high-altitude-dwelling donors increased a little or not at all. In contrast, RBC counts from high-altitude dwellers with chronic mountain sickness increased 60-fold.

This result led the researchers to question why people with chronic mountain sickness produce so many extra RBCs in response to low oxygen.

In a previous study, the team had compared the genomes of high-altitude dwellers with and without chronic mountain sickness. This revealed a gene that varied between the 2 groups—SENP1, which is increased in low-oxygen situations in people with chronic mountain sickness but not in healthy individuals.

In the current study, the researchers set out to determine if SENP1 plays a role in high-altitude adaptation.

The team inhibited the SENP1 gene in iPSCs from patients with chronic mountain sickness. As a result, excessive RBC production was reduced by more than 90%.

When the researchers added extra SENP1 to healthy, adapted highlander iPSCs, RBC production increased 30-fold, nearly recapitulating that seen in patients with chronic mountains sickness.

Further experiments revealed how SENP1 affects RBC production. Elevated levels of the enzyme in chronic mountain sickness boost levels of several other proteins that promote cell division and survival, including VEGF, GATA1, and Bcl-xL.

“We’re interested in determining the early steps in this process—how low oxygen triggers SENP1 in the first place,” said study author Priti Azad, PhD, of the University of California San Diego School of Medicine.

“We are also investigating how existing altitude sickness medications, such as Diamox, work and whether or not it’s through this same mechanism.”

Study provides new insight into RBC production