Molecular Biology
No Other Way Out for Iron

Infectious Disease
Milestone Reached, But Campaign Against Polio Continues

Developmental Biology
Stem Cell Niche Discovered in Placenta

Medical Practice
Dual Loyalties at Abu Ghraib: Squeezing Ethics out of Care

Leak-patching Protein Shuts Down Tumor Growth, Swelling

Specialization Seen in Chromatin Remodelers

Study Plays Cat and Mouse with Development of the Visual Cortex

Proceedings of the HMS Faculty Council

Donor Funds Labs for Aging Research

MassCURE to Advocate for Regenerative Medicine

Lemelson Prize Awarded for Innovations in Cancer and Stroke

Match Day Links One Third of Fourth-years to Internal Medicine Residencies

Honors and Advances

Consortium Formed for RNA Interference

AIDS and Isolation Among the Navajo

Front Page

Stem Cell Niche Discovered in Placenta

Insight on Cell Expansion May Benefit Bone Marrow Transplants

Stem cells are the Peter Pan of the cellular world, caught in a state of perpetual possibility, refusing to grow up and commit to a particular path. But to maintain this elusive quality, the cells need their Neverland, a safe niche in which they can grow and divide without being nudged along the path of commitment. When stem cells are taken out of these safe harbors, as when they are cultured in the lab, they quickly die or differentiate into distinct cell types. If scientists could better understand these niches, they would have an easier time recreating a Neverland for stem cells in culture.

Pockets of potency. A study of the kinetics of blood stem cell populations in the mouse embryo shows that a large pool of stem cells forms in the placenta for about three days during development before the majority collect in the fetal liver. The x axis shows embryonic days, and the y axis shows long-term repopulating units, a calculation of the stem cells in each tissue able to repopulate the blood cells of irradiated mice for more than 10 to 12 weeks after transplantation. An image of a mouse embryo, inset, shows the location of known stem cell sites. (Graph and image adapted by Rachel Meyer)

In the March Developmental Cell, a study in mice identifies a new niche for blood-forming stem cells during fetal development: the placenta. The research, led by Hanna Mikkola and Stuart Orkin, solves the longstanding riddle of where the cells that form the hematopoietic system come from. The paper is one of two published in the same issue that independently report the findings. Together they suggest that the placenta has special stem cell–promoting properties that if harnessed in vitro, could help in cultivating cells for bone marrow transplantation and other uses.

Niche Product
In adults, the bone marrow has specific niches for expanding stem cell populations and differentiating cells into different types. “It is a perfect factory for making blood cells,” said Mikkola, HMS instructor in pediatrics at Children’s Hospital Boston. But in early fetal life, “you don’t have these fancy microenvironments ready in the embryo,” she explained. Instead, the fetus must find makeshift places suitable for storing, growing, and differentiating its cells.

The first blood cells to form are actually red blood cells made in the embryonic yolk sac; the stem cells come later. Hematopoietic stem cells have previously been detected in two sites during development in mice: the aorta-gonad-mesonephros (AGM) region and later the fetal liver, where a large pool of stem cells accumulates until it is transferred to the bone marrow around the time of birth. It always seemed doubtful that the liver’s entire stockpile could burgeon suddenly from the few cells in the AGM. “People have been wondering, where are the missing stem cells?” Mikkola said.

“A stem cell can only be as good as its environment is,” said Hanna Mikkola, and much can be learned from studying the environments that nurture them. (Photo by Steve Gilbert)

The idea that they may be hiding in the placenta came from the team’s collaborator Francoise Dieterlen-Lièvre, the French scientist who first discovered hematopoietic stem cells in the AGM 25 years ago. She had been studying blood cell development in birds and found that a structure in the embryo, the allantois, serves as a reservoir for stem cells. In mammals, the allantois is a small peninsula of tissue in the embryo’s middle cell layer that fuses with the outer layer of cells, forming fingers of tissue that create the fetal side of the placenta. Dieterlen-Lièvre’s lab performed initial studies on mammalian placental cells suggesting that the placenta could also harbor undifferentiated blood cells, but whether true stem cells were present remained uncertain.

Identity in Action
Stem cells do not have an easily recognizable form; they must be verified by their function. The only way to find hematopoietic stem cells for sure is to transplant a sample into irradiated mice whose hematopoietic systems have been eradicated and see if the cells can reconstitute bone marrow with new blood cells. Mikkola and graduate student Christos Gekas used this method to detect stem cells in the placenta from about the tenth day of development, as early as cells found in the AGM. By transplanting different fractions of the placenta, they were able to quantify the stem cell populations. The researchers found that the placenta houses a very large pool of cells for two to three days, which quickly disappears as the liver’s supply expands.

“The number of stem cells [in the placenta] seems to exceed any other place we knew about before,” said Orkin, a Howard Hughes investigator and the David G. Nathan professor of pediatrics at the Dana–Farber Cancer Institute and Children’s. “We’re now trying to discover whether the cells are really born in the placenta or whether they come from the circulation and get nurtured there.”

“The number of stem cells [in the placenta] seems to exceed any other place we knew about before.”

Linheng Li, an assistant investigator at Stowers Institute for Medical Research, who wrote a review of the findings, said that the work settles a longstanding debate about the origins of the hematopoietic system. The placenta seems to be a unique environment for rapidly expanding stem cell populations, unlike the liver, where cells are also differentiating. Li said that even bone marrow is more limiting than the placenta, because it supports stem cells but does not encourage them to proliferate. “By comparing these two niches, maybe you could identify some important factors to support the rapid expansion of hematopoietic stem cells,” he said.

The transitory burst of cells in the placenta is gone by birth. But stem cells in umbilical-cord blood are regularly harvested and banked, and might be coaxed to expand. The placenta is known to secrete a range of growth factors and hormones, some of which may provide the secret for growing hematopoietic stem cells while maintaining their perpetual “stemness,” as Mikkola terms it. “Stemness is a quality that’s very hard to achieve,” she said, “and it’s very easy to lose.”

—Courtney Humphries

top