Thesis live 1.1 The stem cell niche

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

1.1 Stem cells and regenerative medicine

The concept of the stem cell niche was first proposed theoretically by Schofield exactly 30 years ago in the context of hematopoietic stem cells: “a hypothesis is proposed in which the stem cell is seen in association with other cells which determine its behaviour. It becomes essentially a fixed tissue cell. Its maturation is prevented and, as a result, its continued proliferation as a stem cell is assured. Its progeny, unless they can occupy a similar stem cell ‘niche’, are first generation colony-forming cells, which proliferate and mature to acquire a high probability of differentiation, i.e., they have an age-structure.”

Niches are restricted and specialized tissue microenvironments that integrate local and systemic signals for the regulation and maintenance for resident stem cells. The elements of the stem cell niche include the constraints of the architectural space, cellular components like stromal supporting and descendent/progenitor cells and acellular elements, like soluble and membrane bound molecules, paracrine and endocrine signals from local or distant sources and neural input [Figure by Jonas].

Niches are dynamic entities, could be redistributed and ideally “a candidate niche

Thesis live: 1.1 Turnover or Every cell has a lifespan

In the live thesis building blogxperiment I edit (digest, compile, write, rewrite, delete) my ongoing doctoral thesis in blog posts and put the parts together on thesis live. The title: The physiologic role of stem cells in tissues with different regenerative potential.

1.1 Stem cells and regenerative medicine: basic concepts

/turnover: cellular turnover/

The concept of biological turnover (rate) can be interpreted on many levels: molecules, molecular pathways (signaling), organelles, cells, tissues, organs. The turnover rate by which a biological entity is replaced can be quantified by measuring its half-life. /In abstract form “the half-life of a quantity whose value decreases with time is the interval required for the quantity to decay to half of its initial value” (Wikipedia) I have to check whether it is problematic to explicitly use a Wikipedia entry - I am sure it is used implicitly - in a PhD thesis/ The concept of half-life refers to the time required for an initial quantity of entity E to decay half of its initial value. According to Caplan [reference]: “Every cell in the body has a specific half-life; every cell comes to maturation and will, predictably, drop dead in due course.” For instance erythrocytes have half-lives of 60-90 days and the turnover rate of hepatocytes is 1-2 times/year. On Figure 1 from Caplan the lineage development of a differentiated cell and its replacement cell is delineated. The relative position of these two curves to one another defines growth, steady-state, or atrophy depending on when the first cell dies and when its replacement, the second cell, comes online. /I am not sure here how to solve the problem of legends in the case of figures coming from the literature but I figure it out, here is/

Oxygen control of stem cell niches and cell fates

Did you know that physiological normoxia generally falls in the 2-9% O₂ (14.4-64.8 mm Hg) range for most adult cells in vivo? 3 remarkable exceptions are thymus, kidney medulla and most importantly bone marrow which can exist at 1% O2 (7.2 mm Hg). On the other hand, stem and progenitor cells are frequent residents of hypoxic niches and low O₂ regulates their differentiation. Conclusion?

Although most cells are maintained in culture conditions at 21% O₂, this is unlikely to be optimal for maintaining their normal proliferative or developmental state. The derivation of novel stem and undifferentiated cell populations should therefore be enhanced by culture in the range of 3–5% O₂.

More on this very important and usually neglected oxyphsiological angle on stem cells, development and culture in the very uptodate review: The role of oxygen availability in embryonic development and stem cell function by Simon@Keith in Nat Rev Mol Cell Biol. 2008 Apr;9(4):285-96.

Some stem cells (such as those in the endosteal bone marrow compartment) occupy extremely low O2 microenvironments (<0.5% O2)

Friday Gumbo Journal Club: hESC line differences and a killer MSC review

It’s Friday, that is a lunch heaven for a Gumbo loving biogeek at Tulane:

Stem Cell Express: Copy Number Variant Analysis of Human Embryonic Stem Cells from the Teitell Lab (It’s good to see that CIRM funded results and papers are coming out):

induced Pluripotent Stem cells from a 69 year old human: the hidden story?

The successful reprogramming (dedifferentiation) of differentiated human somatic cells into a pluripotent, embryonic stem cell-like state called induced pluripotent stem cells (iPS) using just 4 (and recently 3) introduced transcription factors is the biggest news of current stem cell biology. In the paper published in Cell by the Yamanaka group (Takahashi et al.) the iPS clones derived from the facial dermis of a 36-year-old Caucasian female were highlighted. Out of 50 000 retrovirally transduced fibroblasts 10 hES cell-like colonies were observed. But what I found really thought provoking (and poorly discussed in the blogosphere) is that with the same approach iPS cells were generated from the synovial tissue of a 69-year-old Caucasian male. Interestingly out of 50 000 modified cells 17 hES cell-like colonies were found. This finding could easily be relevant from a stem cell aging point of view.

During ageing there is an overall decline in tissue regenerative potential, but it is not clear whether it is due to the intrinsic exhaustion of the adult tissue stem cells or the diminished functionality of the stem cell niche or a change in the systemic milieu. Answers could be different - tissue by tissue.

But if a terminally differentiated connective tissue cell, like the synoviocyte above could be completely reprogrammed from a 69 year old, otherwise health individual into a pluripotent state….well it could it be interpreted as an argument against the cell-intrinsic genetic aging program in adult and aged connective tissues with some cautions.

Caution 1: What if the source of the iPS cells were not really terminally differentiated, but undifferentiated stem or progenitor cells coexisting in fibroblast culture. This problem has been discussed in the paper and forms the Achilles’ heel of it.

Caution 2: The reprogrammed iPS cells from an aged person are behaving the same way as the iPS cells from a younger person with no additional cellular aging characteristics.

As the critical tail of almost every peer-reviewed paper used to say: Further study is needed.

Here is the paragraph on the synoviocytes and the tables and figures are in the supplemental data.

George Daley explains the source of Hwang’s “cloned” ES cells on Youtube

George Daley, the new president of the International Society for Stem Cell Research explains shortly the notorious case on a not embeddable (??????) YouTube video. If you are too busy to read the story, than watch it, it is 2 minutes and 13 seconds. Thanks for the video tip, Alexey Bersenev.

If you have a bit more time to read on:

Hwang’s “clone” was really a parthenote, Daley reports

Microvesicles in cell-to-cell communication

This slide is from my morning Journal Club presentation at our Tulane Lab.

Here are 3 papers if you are interested in the “microvesicles” phenomenon.

Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.