Researchers have successfully used adult human stem cells to coax new blood vessel growth and restore blood flow in mice with artery damage to their legs.
The study provides important clues behind the therapeutic properties of these cells, which have already shown promise in early human trials for treating peripheral arterial disease (PAD), a debilitating condition that can require amputation of affected limbs.
A unique fraction of stem cells from human bone marrow boosted recovery in mice that had a femoral artery removed beforehand to cut off blood supply to one of their legs. Researchers isolated the cells based on high expression of an enzyme called aldehyde dehydrogenase (ALDH high), which they then labeled with fluorescent trackers before injection into the mice.
Imaging techniques showed that the cells targeted the limbs with reduced blood supply, otherwise known as ischemia. These cells enhanced both blood flow and new blood vessels compared to mice that received unpurified bone marrow cells or fractions without the special stem cells.
“Faster blood flow recovery is likely to translate into better tissue recovery,” said study co-author Daniel Link, an associate professor at Washington University School of Medicine in St. Louis, in an e-mail interview. “One of the major limitations to cell-based therapeutic angiogenesis is our lack of understanding of the cell types that mediate this response. This study identifies a new subtype based on an easy to perform assay (ALDH activity) that can stimulate angiogenesis. Isolating ALDH high cells prior to delivery to ischemic tissue may dramatically improve efficacy.“
The researchers believe their study, published in the May 21 issue of the journal Blood, supports the potential use of these cells as a new line of treatment for PAD. The chronic condition, which is common in older adults with diabetes, is caused by build up of fatty deposits that block arteries supplying blood to the extremities and some organs. In its most severe form, called critical limb ischemia (CLI), poor circulation in the legs can cause pain, weakness and tissue damage.
“Unfortunately, some of our PAD patients may have had open bypass surgery or less invasive procedures [like stents] that failed to salvage their limbs. Other patients can have such severe arterial disease where a bypass or revascularization procedure is not possible,” said Nasim Hedayati, an assistant professor at the UC Davis department of surgery who was not involved in the study, in an e-mail interview.
“Therefore, the possibility that advances in stem cell research may one day help form new blood vessels in ischemic limbs is very exciting. Being able to prevent a patient from losing a limb can greatly affect his or her quality of life and survival.“
The study results are directly relevant to humans, the researchers said.
“We use immune deficient mice so we can study the function of human cells in an animal model of CLI. These studies allow for ‘proof of principal‘ that human cells can regenerate blood vessels after transplantation,” said senior author David Hess, an assistant professor at the University of Western Ontario, in an e-mail interview.
Study author Jan Nolta likens the ALDH high cells to “paramedics of the body” because they directly migrate to tissues damaged by reduced blood flow and secrete factors that promote angiogenesis. She and her colleagues recently submitted a report for publication in which they identified the key molecules – called chemokines – that drive this unique homing behavior.
“If we knock out the receptors for those [chemokines] in the stem cells, then the stem cells can’t migrate anymore,” said Nolta, a professor of internal medicine and director of the UC Davis Stem Cell Program.
Unlike embryonic stem cells, which can replace any type of specialized cell in damaged tissue, the adult stem cells in the study did not stick around once they initiated repair.
“After a couple weeks, they really aren’t needed anymore because the tissue itself takes over,” Nolta said. “They’re just there for a couple of weeks to tip the balance towards healing instead of [cell death].“
The researchers have not yet isolated a single cell type or secreted factor responsible for the ALDH high population’s regenerative properties, but they are confident that the intact stem cell mixture will suffice for clinical purposes.
“If we can understand how the stem cells induce regeneration, we will be better equipped to develop rational clinical therapies for a wide variety of diseases,” Hess said.
ELAINE HSIA can be reached at campus@theaggie.org.
