Adults
Bone cells such as osteoblasts and osteocytes that form the bone through different cellular processes are derived from bone stem cells. Stem cells are classified into different type based on their potency. Potency is defined as the ability of stem cells to differentiate into different types of specialized cells. Mesenchymal stem cells (MSCs) are said to be multipotent stem cells, meaning they can differentiate into all specialized cells found in the body.
Between the cascade of intracellular changes that lead to the formation of specialized cells from stem cells, there exists an intermediate state called the precursor or progenitor cell. The progenitor cells are unipotent or oligopotent cells—they can form only one to three kinds of specialized cells. They are mostly in the human body at the specific tissue site whose cell type they can differentiate into. The purpose of these cells is to heal and regenerate tissue damaged from disease and trauma. A unique characteristic that sets apart stem cells from progenitor cells is the ability to self-renew. Progenitor cells can divide to renew and maintain their oligopotent state only a finite number of times. At other times, they divide asymmetrically to produce specialized cells based on their niche. Intestinal cells contain progenitor cells in the pit of the glandular epithelium and, in the event of injury, these cells move up to differentiate into intestinal epithelial cells.
The formation of bone in the developmental process contains two definitive segments. One is the formation of cartilage and following that is the invasion of this cartilage by osteoblasts, which form the bony matrix. The cartilage provides structure for the osteoblasts on which they form bone. Cartilage is mostly generated from the differentiation of chondrocytes that are formed from differentiation of the hematopoietic stems cells or bone progenitor cells. Additionally, the three subclasses of cells that are necessary for the formation of bone during development are osteoblast, osteoclast, and osteocyte. Osteoblasts are responsible for the absorption of calcium and deposition in the matrix to clarify the bone, osteoclasts reabsorb the cancellous bone leaving way for osteoblasts to deposit new bone. Osteoclasts are formed from the hematopoietic monocytic cells while the osteoblasts are generated from osteoprogenitors. Osteocytes are generated from osteoblasts and they are encased in a mineralized matrix with hydroxyapatite, calcium carbonate and calcium phosphate that is deposited around the cell. Osteocytes are not mitotic and mostly live in the bone as long as the organism is alive.
Osteoprogenitors
Bone is primarily formed from specialized cells called osteoblasts. It contains osteoblasts and calcified matrix, which are characteristic. The osteoblasts are generated from mesenchymal stem cell differentiation in the fetal stages. Bone is also one of the human organs that undergoes remodeling constantly and has the ability to regenerate and heal during the adult life. Ability to regenerate and heal is mainly due to the presence of progenitor and mesenchymal stem cells in the bone that differentiate into osteoclasts. The osteoprogenitors, or bone progenitor stem cells, are an intermediate stage between MSCs and differentiated cells, and they are oligopotent cells that have the ability to differentiate into fibroblasts, osteoblasts, adipocytes, chondrocytes, and muscle cells based on the environmental signaling cues. They differentiate into osteoblasts on the expression of a key transcription core binding factor alpha-1 (CBFA1). This transcription factor activates genes that are part of the pluripotency network critical to the differentiation into osteoblasts. Expression of other factors such as bone morphogenic protein (BMP) also induce the differentiation to osteoblasts. BMP-7, belonging to the BMP family of proteins, initiates the differentiation of osteoprogenitors to osteoblasts that mature into bone-forming cells that deposit calcium and mineralize the matrix by forming hydroxyapatite as found in the bone. Apart from hormonal induction, electromagnetic fields have been shown to enhance the ability of osteoprogenitors cells to differentiate. High-frequency pulsed electromagnetic field application to fracture sites has been shown to expedite the healing process. The mechanism of action is closely related to improving rate of cell cycle, thus promoting the cells to differentiate faster.
Adult Progenitor Cells
Osteoprogenitors are present in the periosteum (the outer lining of the bone), endosteum (the inner lining of the bone and bone marrow), and in the osteonal canals (crevices in the compact bone). As mentioned above, the osteoprogenitors differentiate into osteoblasts to differentiate into osteoblasts that facilitate bone remodeling and regeneration. The endosteum that lines the inner wall of the bone marrow contains osteoprogenitors, and the hematopoietic stem cells that are secreted in the bone marrow are a heterogeneous mixture that contain osteoprogenitors as well. Bone marrow aspirates are an autologous source of osteoprogenitor cells.
Once isolated from the marrow, when sorted based on functionality, the progenitor cells can be differentiated to osteoblast-generating cells in vitro for further therapy. Since the bone marrow produces osteoprogenitors, there is a probability that these progenitors enter the blood stream along with the other blood cells and hematopoietic stem cells. In 2007, a group of researchers found that osteoprogenitors were circulating in the blood. Most tissues have a reserve of these progenitors in order to create bone in the event of injury. They isolated these cells from human blood samples and the progenitors were characterized based on the markers they expressed. Levels of these osteoprogenitors were higher in patients with fibrotic diseases, which are characterized by the presence of extraskeletal tissue. This could be a congenital defect where the toes and fingers are not individual digits and there is extraskeletal tissue in the midst. The circulating cells after isolation were propagated in vitro and differentiated into bone cells, which were later used in conjunction with biomaterials for transplants.
One of the other easily accessible organs that contain osteoprogenitors is the periosteum of the jaw. It contains three layers, and the innermost layer contains an abundance of bone progenitor cells. These progenitor cells are isolated through maxillofacial biopsies and the cells are separated based on the markers expressed. These cells are then expanded in vitro and differentiate to osteoblasts. These osteoblasts are used in reconstruction of the jaw. It is also an effective tool for use in facial reconstruction and it eliminates the issue of immunogenicity.
Another location where the osteoprogenitor cells are present in the body from where they can be easily aspirated is the vertebral column. The vertebral column contains four layers and osteoprogenitors can be isolated from all four layers to obtain a sizable quantity. These cells are used for regenerative therapy and cell replacement purposes. Since the vertebral body is a great source, they will augment spinal fusion surgeries.
Current Technology
Osteoprogenitor cells found in the bone marrow and the periosteum are not sufficient in number for direct therapeutic purposes. The cells need to be expanded ex vivo and one of the significant disadvantages is the limited number of divisions. Several technologies have and are being developed to expand the cell ex vivo to create a panel of progenitors or osteoblasts that can be used. Companies are using an automated cell expansion system to develop these lineages. The process of automation and the need of exogenous factors will be standardized. The second phase is to test the ability of these cells to form blood vessels. Moving to the third phase from this point, the ability of these cells to heal fractures in the mouse model will be tested. Upon successful completion of the third phase, the same will be tested in phase I and II clinical trials in which the ability of these cells to heal nonunion fractures will be tested. The end product will be a therapeutic kit that aids cell replacement for healing nonunion fractures.
Sharanya Kumar
Independent Scholar
See Also: Bone: Current Research on Isolation or Production of Therapeutic Cells; Bone: Existing or Potential Regenerative Medicine Strategies.
Further Readings
Chaudhary,
