Through a series of writings about bones, we have seen that most bones are covered on the outside by dense cortical bone (compact bone), while the inside is composed of tiny pillars of bone called trabeculae, creating spaces in between that give rise to a sponge-like structure known as spongy bone (cancellous bone). The empty spaces within this spongy bone—shaped somewhat like uneven, randomly stacked breakwaters along the seaside—are filled with bone marrow.
Bone marrow is divided into two types: red marrow and yellow marrow. The red marrow is responsible for producing blood, while the yellow marrow contains abundant fat cells and thus appears yellow. It is within the spongy bone’s hollow spaces, filled with red marrow, that hematopoietic stem cells (HSCs)—the stem cells responsible for generating various blood and immune cells—reside.
Stem Cells
In previous articles, we learned that osteoblasts, the bone-forming cells, are derived from mesenchymal stem cells (MSCs), whereas osteoclasts, the bone-resorbing cells, belong to the monocyte/macrophage lineage and ultimately originate from hematopoietic stem cells. Later, we will also discuss how osteoblasts help regulate hematopoietic activity by maintaining hematopoietic stem cells in a dormant state, thereby preserving their population.
This close interaction suggests that mesenchymal stem cells and hematopoietic stem cells are intricately interwoven. To better understand their relationship, I decided to delve further into their developmental origins—from the earliest stages of embryogenesis. This exploration also forms a crucial foundation for understanding immune cells, which will be discussed in future writings.
From the earliest fertilization stage, various types of “stem cells” appear throughout the embryonic development process. These stem cells are classified according to the range, intensity, or capacity—referred to as potency—with which they can differentiate into other cell types. Ultimately, to understand hematopoietic stem cells and the immune cells they generate, we will also explore the different types of stem cells and develop a general understanding of stem cell biology along the way.
Embryo — The Starting Point of the Fetus
When a sperm and an egg unite, they form a zygote. Within the zygote exist two nuclei, one from each parent, each containing 23 chromosomes—these are called pronuclei. When these two pronuclei fuse within the same cytoplasm, cell division begins. A single cell divides into two, two become four, and the number continues to increase rapidly. At this stage, cell number is more important than cell size. Up to the eight-cell stage, the divided cells (blastomeres) have the ability to form both the embryo and extraembryonic structures (such as the placenta). Each of these cells can therefore develop into a complete organism—a property known as totipotency. In other words, the cells at this stage are called totipotent stem cells, meaning they have the capacity to give rise to all types of cells. Here, totipotency is specifically defined as “the ability to develop into a complete organism.” This distinction is crucial: because totipotency exists only in natural early embryonic stages, defining it merely as “the ability to differentiate into any cell or tissue” blurs the boundary between totipotent and other, lower-level stem cells. [1]
The illustration below shows the stages of human embryonic development during the first few weeks. After about eight weeks following fertilization, the major organs and basic body structures have formed. From this point onward, the developing organism is called a fetus, and the organs that have begun to form will continue to mature and grow.
From the Bilaminar Structure to the Three Germ Layers
After implantation into the uterine epithelium, the blastocyst undergoes an important process in which it forms the three germ layers that will develop into all the tissues and organs of the human body. The cluster of cells inside the blastocyst, corresponding to the bunch of grapes mentioned earlier, begins to differentiate into two flattened layers. Since this structure is composed of two layers, it is called the bilaminar germ disc. When observed in cross-section, the upper layer is called the epiblast, and the lower layer is the hypoblast. The epiblast gives rise to all the embryonic cells that will form the body itself, while the space above it becomes the amniotic cavity. The hypoblast does not contribute directly to the body of the embryo but instead forms the yolk sac, which temporarily provides nutrients and primitive blood to the early embryo.
Gastrulation: Formation of the Three Germ Layers Through Cell Migration
The basic cell layers that form all the tissues of the human body are called germ layers, and they consist of three types: endoderm, mesoderm, and ectoderm. The process by which these three layers are formed from the epiblast is called gastrulation, which occurs around the third week after fertilization in humans. Let us now examine how the three germ layers are formed through the process of gastrulation.
The beginning of gastrulation is marked by the appearance of the primitive streak at one end of the epiblast. [2] As the embryo develops, the primitive node and the primitive streak establish the body’s axis. The side where the primitive node forms becomes the cranial or head end, and the side with the primitive streak becomes the caudal or tail end. As some cells in the primitive streak undergo apoptosis and lose adhesion, a long groove forms along the streak. Cells of the epiblast move inward through this groove, migrating downward to replace the original hypoblast located beneath. Through this large-scale movement, almost like a great migration of cells, the hypoblast is displaced downward and surrounds the inner cavity, forming the primitive yolk sac.
Even after the hypoblast is replaced, the cells that migrated inward from the epiblast continue to move deeper to form an additional middle layer. As a result, the previously two-layered structure becomes three layers. The first cells that replace the hypoblast form the endoderm, the newly formed intermediate layer becomes the mesoderm, and the remaining cells of the epiblast that do not migrate form the ectoderm.
The reason we have examined the process in such detail up to this stage is to understand the formation of the three germ layers. These three layers form the foundation for all tissues and organs of the human body. Even after the completion of embryogenesis, throughout our lifetime, the origin of various tissues from these layers continues to have great significance. The ectoderm differentiates into the epidermis and the cells of the central nervous system, the mesoderm gives rise to bones, blood, muscles, cartilage, and adipose tissue, while the endoderm differentiates into the epithelial cells of the liver, pancreas, lungs, and gastrointestinal tract.
Mesodermal Subdivisions
Among these three germ layers, we will now take a closer look at the mesoderm, which is directly related to the formation of bones and blood — the main focus of this discussion. The mesoderm lies between the ectoderm above and the endoderm below, and can be subdivided into three regions centered around the notochord and the neural tube. The neural tube, located above, originates from the ectoderm, and the notochord, formed just beneath it, will later develop into the gelatinous nucleus pulposus at the center of the intervertebral disc, serving as a shock absorber in the adult spine. During embryonic development, however, the notochord functions as the central axis of the developing body. Based on this axis, the mesoderm can be divided into three regions: the paraxial mesoderm (located symmetrically on both sides of the neural tube), the lateral plate mesoderm (the outermost region farthest from the axis), and the intermediate mesoderm situated between the two.
Paraaxial mesoderm and somites
The paraxial mesoderm, as the name suggests, lies on both sides of the central axis. When viewed from the dorsal side of the embryo, it appears as two symmetrical bands flanking the neural tube, which has originated from the ectoderm. These bands eventually segment into small spherical clusters of cells that will form parts of the body. Each of these segments is called a somite. This process can be likened to dividing a large piece of dough into smaller pieces to make individual loaves of bread. Depending on the type of signals received from surrounding tissues and their positional context, somites differentiate into various body structures. Somites are further categorized into sclerotome, dermatome, myotome, and syndetome. The sclerotome differentiates into skeletal structures such as vertebrae, ribs, and intervertebral discs; the dermatome gives rise to the dermis of the skin; the myotome forms skeletal muscles of the back, trunk, and limbs; and the syndetome develops into tendons and ligaments.
Lateral plate mesoderm and intermediate mesoderm
The lateral plate mesoderm, as seen in the illustration, splits into two layers separated by a cavity. The outer (upper) layer forms the somatic layer, which is adjacent to the ectoderm, while the inner (lower) layer forms the splanchnic layer, which is adjacent to the endoderm. Although the first illustration shows only part of this process, the ends of the ectoderm and endoderm meet and form a circular boundary as shown in the lower diagram, enclosing the coelomic cavity. This cavity, or coelom, will later develop into the large internal body cavities that house the major organs — such as the thoracic and abdominal cavities that contain the heart, lungs, stomach, and liver. The innermost endoderm folds inward to form the primitive gut, and the splanchnic layer adjacent to it develops into structures such as the adrenal cortex, spleen, smooth muscle of the digestive tract, cardiovascular system, and hematopoietic organs. Meanwhile, the somatic layer in contact with the ectoderm forms the body wall, which corresponds to the outer framework of the body and later gives rise to the bones of the limbs. Between the paraxial mesoderm and the lateral plate mesoderm lies the intermediate mesoderm, which serves as the precursor to the urogenital system, differentiating into organs such as the kidneys, ureters, gonads, and reproductive structures.
[References]
[1] Totipotency: What It Is and What It Is Not
doi: 10.1089/scd.2013.0364
[2] Embryology, Gastrulation
https://www.ncbi.nlm.nih.gov/books/NBK554394/?utm_source=chatgpt.com
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