Stem Cell Chicken And Egg Debate Moves To Unlikely Arena: The Testes
Main Category: Stem Cell ResearchAlso Included In: Biology / Biochemistry; Seniors / Aging; Cancer / Oncology
Article Date: 22 Jul 2008 - 3:00 PDT
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Logic says it has to be the niche. As air and water preceded life, so the niche, that hospitable environment that shelters adult stem cells in many tissues and provides factors necessary to keep them young and vital, must have emerged before its stem cell dependents.
A team of scientists at the Salk Institute for Biological Studies led by Leanne Jones, Ph.D., assistant professor in the Laboratory of Genetics, now suggests that this is not always the case. They report in the July 20 advance online edition of the journal Nature that the cells that comprise a specialized niche in the testis of fruit flies actually emerge from adult stem cells, a finding with implications for regenerative medicine, aging research, and cancer therapeutics.
Previously, investigators thought that a fruit fly's allotment of testis niche cells was handed out at birth and meant to last a lifetime. "What this paper demonstrates is that once a fly becomes an adult, some stem cells that function in spermatogenesis start making the very cells that support them," said Jones. "Once a fly develops into an adult, some of these niche cells can be replaced."
Using microscopy and fluorescent markers enabling them to image specific cell types over time, Jones' group, led by first author Justin Voog, actually caught a testis stem cell population in the act of turning into their own niche, known in the fly testis as the hub.
"We used a detailed lineage tracing strategy to differentiate between single somatic stem cells (SSCs) and hub cells," said Voog, an M.D./Ph.D. student in Jones' lab. The hub contains approximately 10 cells that secrete factors promoting self-renewal of two neighboring stem cell populations - germline stem cells, which become sperm, and SSCs, which develop into a structure that encapsulates maturing sperm. "We tracked cells over a period of days and saw that SSCs can generate not only other immature SSCs but their niche support cells," said Voog. By contrast, germline stem cells appeared incapable of generating hub cells.
Their study also explores the molecular basis of stem cell/niche interactions. "SSCs in the testis look similar to hub cells," explained Jones. "Both cell types express many of the same proteins." The team experimentally decreased levels of one of those - a sticky surface protein called DE-cadherin that likely allows stem cells to latch on to the support hub - but only in somatic stem cells. When they did so, DE-cadherin expression on hub cells also decreased, providing further circumstantial support for the idea that hub cells emerge from SSCs.
"Stem cell biology is a fast-moving field and insights from model organisms like Drosophila provide great insight into how stem cell behavior is regulated," said Voog. "The architecture of the fruit fly testis makes it an ideal system to address questions about what regulates stem cell interactions within the niche."
Jones agrees, noting that spermatogenesis is also a great system to manipulate experimentally. "Spermatogenesis is less complex than stem cell systems that give rise to multiple cell types, such as blood stem cells," she said. "Only one cell type emerges from the process - sperm - so if something goes wrong with the system it is readily apparent: you won't form any sperm."
According to Jones, mammalian stem cell niches are not so well characterized. Although their whereabouts in tissues like brain or bone marrow is known, how niche compartments relate to their respective neural or blood stem cell charges is an open question.
Issues raised by this study will have to be addressed in humans before good stem cells are exploited or bad ones are eradicated. Will stem cells transplanted in proposed regeneration therapies establish their own support crew or will a "niche transplant" be required to maintain them?
Or, do so-called cancer stem cells, which are thought to form the root of most tumors, create a structure analogous to the niche, and if they do, could it be targeted as anti-cancer therapy?
Jones says the onus is now on mammalian stem biologists to answer these questions. "In mammals the field is still at the point of identifying a stem cell, which precedes characterizing the cells that support them," said Jones. "In our system we can definitively say that some stem cells can create a microenvironment that enables them to survive. If I had to say whether similar processes occur in mammalian cells, I'd guess yes."
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The study was supported by funding from the G. Harold and Leila Y. Mathers Charitable Foundation, the American Cancer Society, the California Institute for Regenerative Medicine, and the NIH.
Also contributing to this study from the Jones lab was Cecilia D'Alterio.
The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.
Source: Gina Kirchweger
Salk Institute
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Which Came First
posted by Denis English Ph.D. on 28 Jul 2008 at 4:43 pmRE: Stem Cell Chicken And Egg Debate Moves To Unlikely Arena: The Testes
Main Category: Stem Cell Research
Also Included In: Biology / Biochemistry; Seniors / Aging; Cancer / Oncology
Article Date: 22 Jul 2008 - 3:00 PDT
Opinion:
The final comment by Dr. Jones is particularly well thought out and adept. I would certainly agree that the interests of evolution essentially require key cells such as stem cells to- if not create- at least contribute to an environment that facilitates their own survival. It is not disputed that the earliest stem cells must perform this function in order to initiate development in all organs; How could multicellular organ development happen otherwise. Surely the first events in development pave the way for subsequent events to proceed, regardless of the terminology we relay upon the cells that initiate these subsequent events. We seem to have justified the notion of calling them collectively "stem cells", even if we don’t really know what a stem cell is. We do know one thing; the term is both convient and attractive, even if it implies the fallicy that our bodies possess populations of identical cells.
But how do we address the adroit comments of Dr. Voog and the question posed by Ms. Kirchweger? Indeed, what came first, the chicken or the egg. Answers to simple questions are inevitably confused by complex terminology. Dr. Voog asserts the fact that the team employed “a detailed lineage tracing strategy to differentiate between single somatic stem cells (SSCs) and hub cells", thereby allowing them to track cells over a period of days whereupon they observed that “ SCs can generate not only other immature SSCs but their niche support cells.By contrast, germline stem cells appeared incapable of generating hub cells".
What does this mean?
Dr. Jones continues to address not the question that Ms. Kirchweger put on the table, but to tout the molecular basis of stem cell interactions with the so called stem cell niche.... "SSCs in the testis look similar to hub cells. Both cell types express many of the same proteins." The experiments support the concept that stem cells latch on to the support hub, and in doing so may facilitate the generation of supportive cells from stem cells.
OK, I’ll buy that as a possible process in development. But what are we addressing here? The genesis of support cells or the answer to the question?
What came first, Gina? The chicken or the egg?
If it were the chicken, then the chickens' support cells would act to endow upon the ultimate stem cell, the egg, properties optimal for survival; properties that clearly exceed the mere need to survive. The purpose of evolution is to advance; and as evolution has progressed, clearly advances have appeared with increased frequency. The situation in fact seems to reflect an evolutionary development that resulted in a process referred to as "facilitated evolution", which certainly may have acquired its own basis from the fundamental aspect that drives evolution, the survival of the fittest.
In primitive organisms, the offspring of the mother and father faced challenges essentially independent of their forefathers, relatives or kin. As evolution continued, offspring were protected not only by their parents, but also by the parents of their parents, their children and their relatives. A clear evolutionary advantage would follow a mutation that facilitated this interaction. Such facilitation would markedly accelerate evolutionary changes preserved by survival.
Other possibilities certainly exist. Perhaps the slow process of evolution, relying on radiation from the sun to engender mutations, led to a mutagenic protein, such that mutation frequency dramatically increased. Selection could then proceed at a faster pace. It is difficult to imagine the evolutionary advantage any such a protein could initially convey, but selection depends on persistence, and the DNA that generates any protein which conveys any survival advantage is a candidate for genetically encoded evolutionary advance, even if the immediate effects are detrimental. Given the relatively short leap from amphibian to man in contrast to the persistent longevity of green algae, it is readily apparent that facilitated evolution markedly impacted on the development of advanced species.
Which brings me back to the question at hand; which came first, the chicken or the egg.
To me, the answer is obvious(see reference 1). We think of the egg and of immature stem cells as primitive cells, under the unfounded notion that somehow, these primitive cells are able to produce more advanced cells. We think that cellular specialization, functional or structural, defines this advance. Surely a neuron is more advanced than a stem cell; a neuron can respond to stimuli and effect subsequent responses to protect the host. Any secretory cell must possess advanced characteristics; if they did not, they would not be able to respond to environmental stimuli. What we forget is that all of the functions of any advanced cells were encoded in the stem cells that produced them.
Far from being a primitive cell, the earliest stem cell had a whole lot of things on its mind when it first divided; some say it had a lot of decisions to make.
“Let me see now, should I generate the cells that will make an arm, or should I go for leg buds? No, forget that, I need to get oxygen into this system so I’ll go for a vascular system. But that may get infected, so why not surround it with phagocytic cells? But then that’s not going to last long unless I get some glucose in here, and its getting dark. What should I do? What cell should I generate?”
Like it had any choice in the matter; any decision to make.
Intuitively, these decisions were all, each and every one, pre-determined. Intuitively, differentiation began at the first division of the fertile oocyte; if it did not, then we would be a mass of fertilized oocytes, all generating identical progeny at every division. If two identical cells result from the first division, why and when and under what influence would differentiation ever begin. Gravity? Nice alternative, but mice reproduce fairly faithfully in outer space. By far the most attractive explanation is that differentiation begins at the first division of the egg. And although this event may be readily reversible, such that essentially identical stem cells are generated from the egg for a few cell divisions, chances are that these cells are not identical at all. Later in development, when the differences are irreversible and readily apparent, we assert differentiation has begun. It is more likely that differentiation begins even before the first cell divides.
Unlike many have purported, stem cells are not immortal; nor is the Universe or nor will ever be any singular organism. But unless we fire one off accidentally, mankind may in fact be immortal; surely the Universe is. And it is so as it captures the optimal components of the aging Universe, collates them and draws them together until they expand into a new, pristine Universe.
This analogy is not lost on mankind. Stem cells draw the optimal components of the aging organism in order to produce a better stem cell, a better egg, the latter being the purpose of life. The stem cell, the sperm and the egg are the most advanced cells of the organism, and they perpetuate the progression of the species by performing highly complex functions that dictate their fate. One of these functions may certainly be to facilitate the generation of cells that assist stem cells in their ominous duties during development, as the researchers cited above suggest.
What came first; it was the egg, Of this there can be no doubt.
Denis English, Ph.D.
Founding Editor, Stem Cells and Development
Citation:
1)English, D and PR Sanberg. Neural specification of stem cell differentiation. Stem Cells Dev. 15:139–140 (2006).
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