Bone Progenitor Cells Discovered – Might Help Children Who Need Corective Facial Surgery

In children, bone grow thicker and longer and get stronger and denser. When children reach adolescence, they know that the time has come to stop growing longer and stronger. However, even into adulthood, bones still retain the capacity to heal. Why the differences between adolescents and adults? This is a question that has long fed the imaginations of scientists.

Recently, a collaborative team of biomedical researchers from the University of Michigan, Kyoto University and Harvard University has made the answer to this question a little clearer.

Dr. Noriaki Ono, U-M assistant professor of dentistry, and his collaborators discovered that a certain subset of cartilage-making cells – cells known as chondrocytes – proliferate and differentiate into other bone cells that drive bone growth. These discoveries could lead to new treatments for children with facial deformities who normally have to wait until adulthood for corrective surgery. This study appeared in the journal Nature Cell Biology.

A long-held view is that bone-making chondrocytes die once children reach adolescence and their bones stop growing. However, in adults, bone still heal without the benefit of these bone-making chondrocytes. How does this occur? This question has generated a fair amount of disagreement between researchers.

Ono’s group discovered that some of these bone-making chondrocytes don’t die. Instead, they are transformed into other types of bone-growing and bone-healing cells.

“Up until now, the cells that drive this bone growth have not been understood very well. As an orthodontist myself, I have special interest in this aspect, especially for finding a cure for severe bone deformities of the face in children,” he said. “If we can find a way to make bones that continue to grow along with the child, maybe we would be able to put these pieces of growing bones back into children and make their faces look much better than they do.”

According to Ono, one of the challenges in bone and cartilage medicine is that resident stem cells haven’t really been identified. The only widely accepted idea is that certain stem cells like mesenchymal stem cells help bones heal and other help them grow, but the progenitor cells for these cell populations and what goes wrong with them in conditions such as osteoporosis remains mysterious.

Ono and his team used a technique called “fate mapping,” which labels cells genetically and them follows them throughout development. Ono and others came upon a specific precursor cell that gives rise to fetal chondrocytes, and all the other later bone-making cells and . By mesenchymal stromal cells later in life. Most exciting, Ono and his coworkers found a way to identify the cells responsible for growing bone. By identifying these cells, isolating them and even implanting them into the skull or long bones of a child with a bone deformity condition, the cells would make bone that would also grow with the child.

Many factors cause craniofacial deformities. These types of deformities can place pressure on the brain, eyes, or other structures and prevent them from developing normally. For example, children with Goldenhar syndrome have underdeveloped facial tissues that can harm the developing jawbone. Another bone deformity called deformational plagiocephaly causes a child’s head to grow asymmetrically. Maybe the implantation of such cells can provide a way to restart the abnormally growing bones in these children.

Bmi1 Controls Adult Stem Cell “Stemness”

Stem cell scientists from the laboratory of Ophir Klein at UC San Francisco have discovered a new role for a protein called Bmi1 that might give clues as to how to get adult stem cells to regenerate organs.

Ophir Klein, the director of the Craniofacial and Mesenchymal Biology Program and chairman of the Division of Craniofacial Anomalies at UC San Francisco, said “Scientists have known that Bmi1 is a central control switch within the adult stem cells of many tissues, including the brain, blood, lung and mammary gland. Bmi1 also is a cancer-causing gene that becomes reactivated in cancer cells.”

Crystal structure of the BMI1 protein
Crystal structure of the BMI1 protein

All stem cells are somewhat immature in comparison to their adult counterparts. Stem cells also have the capacity to divide almost indefinitely and generate specialized cells. Bmi1 acts as a molecular switch that, if pushed in one direction, drives stem cells to proliferate and grow, but if pushed in the opposite direction, keeps cell proliferation in check. Research from Klein’s lab now suggests that Bmi1 might prevent the progeny of stem cells from differentiating into the wrong cell types in the wrong location.

Downstream targets of Bmi1
Downstream targets of Bmi1

This new discovery suggests that manipulation of Bmi1 and other regulatory molecules might be some of the steps included in laboratory recipes to turn specialized cell development on and off to create new cell-based treatments for tissue lost to injury, disease, or aging.

Also, the dual role of Bmi1 in pathological settings might be intriguing. Cancers are, in many cases, driven by adult stem cells that behave abnormally. If these stem cells could be differentiated, then their growth would slow. Possibly, inactivating Bmi1 in tumor stem cells might be one strategy.

In these experiments, Klein and his colleagues examined those adult stem cells found in the large incisors of mice. Unlike humans, these teeth grow continuously and are, therefore, an attractive model for stem cell research. Klein explained, “There is a large population of stem cells, and the way the daughter cells of the stem cells are produced is easy to track – it’s if they are on a conveyor belt.” Early in life, human beings possess a stem cell population that similarly drive tooth development, but they become inactive after the adult teeth are fully formed during early childhood.

Mouse mandible showing  the large, paired incisors
Mouse mandible showing the large, paired incisors

In the current study, postdoctoral research fellows Brian Biehs and Jimmy Hu showed that at the base of the growing mouse incisor there is a stem cell population that actively expresses Bmi1. In these cells, Bmi1 suppressed a set of genes called Hox genes. When activated, the Hox genes trigger the development of specific cell types and body structures.

In the mouse incisor, Bmi1 keeps these stem cells in their stem cell state and prevent them from differentiating prematurely or inappropriately. “This new knowledge is useful in a fundamental way for understanding how cell differentiating is controlled and may help us manipulate stem cells to get them to do what we want to do,” said Klein.

As they state in the abstract of their paper: “As Hox gene upregulation has also been reported in other systems when Bmi1 is inactivated our findings point to a general mechanism whereby BMI1-mediated repression of Hox genes is required for the maintenance of adult stem cells and for prevention of inappropriate differentiation.”

Thus this finding from the Klein lab may provide a vital clue for the manipulation of adult stem cells and, perhaps, cancer cells.