This Strange Cancer Of Mine (Part 2)

Human Yolk

As I was waiting for the day of my pituitary MRI, I found it easiest to distract myself by writing posts completely unrelated to Langerhans cell histiocytosis. Eventually, though, curiosity as to the nature of Langerhans cells, in and of themselves, that is, independent of their medical relevance for me, came increasingly to the fore and I found myself diving deeper into the broader world of blood, cancer, immunology, and stem cells. I learned a lot of interesting stuff, which I will try to distill here. Let’s start with stem cells.

Stemness, the potential to “mother” other cell types, is a matter of degree. Cells with the potential to become any of the 200+ adult cell types--plus the yolk sac and placenta—are called totipotent. Totipotent cells are present only during the very earliest stage of embryonic development, from fertilization (zygote) through the first two or three cell divisions. Pluripotent stem cells, which are present from about day 4-7, have almost as much potency as totipotent cells, but cannot generate the extra-embryonic tissue (yolk sac and placenta), nor sperm and eggs. The pluripotent stem cells are commonly referred to as embryonic stem cells.

As embryonic development progresses, more and more cells lose their potential to become something else. Some, though, maintain a high degree of stemness, but to a much more limited degree than pluripotent stem cells. These stem cells are designated multipotent. Multipotent stem cells are often referred to as somatic stem cells, and they retain a high degree of stemness into adulthood, hence their colloquial name—adult stem cells. There are several kinds of multipotent somatic stem cells, each with the potential to “mother” its own distinct array of cell types. The one relevant here has the potential to produce all types of blood cells. They are called haemopoietic stem cells. Haemopoietic is Greek for “blood forming”. For those not much given to ancient Greek, I will refer to them simply as blood stem cells (or, BSCs)

From BSCs to Langerhans Cells

For your yearly physical examination, a blood panel will be generated from your blood sample. A blood panel records levels for a variety of blood cells, crucial for the early diagnosis of many diseases. Red blood cell (erythrocytes) levels will usually appear first on the chart, then blood platelets (thrombocytes), which are in me always borderline low. Then comes the stats for your white blood cells (leukocytes) and then your lymphocytes. Leukocytes are crucial elements of the innate immune response; lymphocytes are the key actors in the adaptive (or acquired) immune response. Here I will focus on the innate immune response, ergo the leukocytes. But first it will be helpful to understand how and where the leukocytes, lymphocytes, red blood cells and platelets are created from BSCs and their familial relationships.

Let’s begin with the traditional picture, in which every type of of blood cell, including mast cells, derive from BSCs in the bone marrow, from which they differentiate through a hierarchical branching process, to become ever more specific types of blood cells, as illustrated in the figure below.

(Focus only on the uppermost branches at the top of the figure and the cell types at the bottom of the figure; the middle zone need not concern us.) In this picture, BSCs (labeled in this figure as “multipotent haemopoietic stem cells”) give rise to two blood cell lineages, one called myeloid, the other lymphoid. Ignore the lymphoid and focus on the myeloid lineage.

The myeloid lineage begins with a cell called the myeloid progenitor, the source of four distinct blood cell lineages: platelets (thrombocytes), red blood cells, (erythrocytes), mast cells (mast cells) and white blood cells (leukocytes). All white cells have a common progenitor, called the myeloblast. Any blood panel will have information about all four types of white blood cells: basophils, neutrophils, eosinophils and monocytes. Langerhans cells derive from monocytes.

A monocyte is so called because it is the only one of the four kinds of white blood cells with a single nucleus. All the rest are multinucleated. Notice that monocytes, like the other white blood cells, don’t finish maturing until they have left the bone marrow and entered the bloodstream. Many monocytes in the blood remain monocytes for their lifetime, which is only a few days. But some monocytes embed in various tissues, mostly the epidermis and lymph nodes. Such monocytes are called tissue resident. Tissue resident blood cells of any kind have much longer lifespans than those that circulate in the blood. While in residence, monocytes have the capacity to become either macrophages or dendritic cells, or in the case of Langerhans cells, some combination of both. So, the final phase of Langerhans cell development occurs in the epidermis. These tissue resident Langerhans cells can spend many years there.

Yolk Sac

This picture of blood cell differentiation depicted in figure 1, is what first shaped my understanding of the origin of Langerhans cells. Imagine my dismay when I learned that recent research indicates that most of my Langerhans cells did not originate in my bone marrow. In fact, my skin was seeded by Langerhans cells long before the bone marrow blood factory developed in my embryonic self. The first LCs to seed my epidermis in fact originated from the yolk sac that surrounded the embryonic me. The yolk sac, you may recall, is extraembryonic tissue. By extraembryonic is meant not part of the embryo itself. The placenta and umbilical cord, which partly derives from the yolk sac, is also extraembryonic tissue. Only the maximally potent stem cells, called totipotent, can produce extraembryonic tissue, along with all cell types of the developing embryo. Totipotent stem cells only exist in the earliest hours of embryonic development, from the single celled zygote through the first couple of cell divisions. After that, no embryonic cell can produce a yolk sac.

The fluid in the mammalian yolk sac, does not at all resemble the yolk of chicken eggs. But like chicken egg yolk, it supplies essential nutrients. The yolk sac is also the ultimate source of a lot of cells that enter the embryo itself. Some become sperm and egg cells, others become blood cells. The yolk sac is the first source of blood cells, including red blood cells and monocyte/macrophages. These monocytes colonize much of the early fetus, including what will become epidermis. Some of the yolk-sac derived monocytes eventually transform into Langerhans cells. Many of the Langerhans cells in my skin are sourced from my fetal yolk sac, before my bone marrow, or BSCs, developed.

After a week or so, my yolk sac passed the blood baton to my fetal liver, along with my first BSCs. My fetal liver remained the primary source of all my blood cells—including those that would become Langerhans cells—until just before I was born, at which point the bone marrow blood-making factory kicked in. But by that time, I was endowed with almost all the Langerhans cells I would ever need. The Langerhans cells in my epidermis since birth, are self-renewing. That is, when some wandered off to the lymph nodes to activate antibody production—upon detecting foreign invasion--the remaining Langerhans cells replaced them. Only when the in-situ replacement wasn’t sufficient, were bone marrow derived monocytes recruited to my epidermis. Once these monocytes became tissue residents, they transformed into Langerhans cells. Call them auxiliary Langerhans cells. These auxiliary Langerhans cells constitute only a small portion of my total Langerhans cell population.

The question I have is this: are the auxiliary Langerhans cells that colonized my skin late in life the culprits, the ones that went rogue? Put another way, are the Langerhans cells that descended from the ones in my skin with which I entered the world innocent? My oncologist seems noncommittal.