A Hierarchy of Stem Cells

Embryonic Stem CellsMost junior scientists prefer to tell us what they know — not what they don’t know. That’s how they are likely to get media attention among their peers and establish their future reputations. But senior scientists and emeritus professors, on rare occasions, are willing to tell us, with humility, what we don’t know, because they have the maturity and self-confidence not to worry about making themselves looking foolish in the eyes of the press or their students. So here is something we don’t know — one of the important open questions in stem-cell biology, and an instance of the genotype-to-phenotype problem: which of two alternative models of stem-cell differentiation determines the architecture of complex creatures?

A second model of stem-cell differentiation during embryogenesis is that there is a hierarchical system of cells with a family of “master” stem cells for individual organs.

(1) Embryonic stem cells derived from the Inner Cell Mass of a blastocyst, a ball of seemingly identical cells derived from a fertilized egg before its implantation in the uterine wall, are known to be pluripotent (able to differentiate into any of three standard germ layers: ectoderm, mesoderm, and endoderm). Under this first model, they are hypothesized to go through a germ-layer stage as they migrate to individual organs during a stage of embryogenesis known as organogenesis, when organs like the heart, the lungs, the brain, and so forth begin to develop. The actions of these different stem cells are then synchronized to create a complete organ.

(2) A second model of stem-cell differentiation during embryogenesis is that there is a hierarchical system of cells with a family of “master” stem cells for individual organs (master stem cells for the heart, master stem cells for the lungs, etc.) that migrate to a location near where they will elaborate the organ they are fated to construct. Only then would they elaborate the nerves, blood vessels, lymph vessels, muscles, and so on that are specific for that organ. Indeed, there may be generals, colonels, captains, lieutenants, sergeants, down to privates who do the real work: in other words there may be a whole hierarchy of organ-specific stem cells that dictate the architecture of the organ itself.

If this second model is true, it could have profound therapeutic implications for how one might employ stem cells to rejuvenate aged tissues. It would mean that we would have to identify the “officer grade” of each patient-derived adult stem cell before it could be amplified into millions of cells and infused or injected into the host tissues.

On the other hand, the last thing that any physician would want to do (following the principle of “Do no harm!”) is to introduce stem cells at the wrong level of differentiation. That might result in a hundreds of multiple malignant teratomas scattered throughout the body.

TeratomaTeratomas are isolated random masses of disorganized tissues. They occur on rare occasions in ectopic pregnancies and may include jumbles of hair, teeth, and cartilage. So it would be crucial to identify these cells by their rank, in terms of their tissue potential. Are they master cells that create the structure of an organ or would they synthesize only one kind of cell? How would we know which was which? Are there cell-surface markers that would distinguish the different types?

We may have the beginnings of the answers to some of these questions. Researchers at the Harvard Stem Cell Institute have identified the early master human heart stem cells from human embryonic stem cells — ISL-1+ progenitors — that give rise to the family of cells that form the full architecture of the heart. [1, 2] This is particularly important because the cells were found in regions of the heart known as “hot spots” for congenital heart disease. These latest human cell findings derive from the work by Kenneth R. Chien (the senior author of the Nature paper) and his team and others in mice.

So, if we are to identify the stage of a master stem cell, we will have to develop new means in vitro for holding them at that stage for amplification so they can be tested with different growth factors or cytokines, and then systematically move them to the next stage of differentiation down a particular desired pathway depending on the planned therapeutic application. Each of these steps will require a deeper understanding of the culture media growth factors than we have now. That’s why Prof. Rudolf Jaenisch, one of the iPSC reprogramming pioneers at the MIT Whitehead Institute in Cambridge, Massachusetts, said “transplantation therapy is far away; but, for some cell types ¬— particularly blood cells, bone marrow, and insulin-producing cells ¬— it might be closer than others.”

Another tricky problem, rarely discussed: what would be the most efficient route of administration for these new cells? (1) Injecting/infusing them into the blood stream IV over several hours in the hopes that they will home-in on the correct organ (and interdigitate themselves into the relevant tissues)? However, this may not happen by itself. (2) Injecting them directly into the tissue? That may not work either. Dropping brand new loose bricks from a helicopter on top of an old brick structure is not the same as having a ground-level mason with a trowel place the new bricks. The original bricks did not fall from the sky, either. The original cells arrived on the scene after a complex, programmed process of embryogenesis, according to a genomically-determined blueprint that exploits a variety of construction techniques, including scaffolding and scaffold removal, which corresponds to Programmed Cell Death (PCD) or apoptosis.

So there are many challenges ahead, and we can’t be sure which problems will be solved easily and which will require a broad creative leap of nanotechnology before these therapies become routine hospital procedures.

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