Transdifferentiation – Stem Cells, Fatty Muscles, and the Role of D3

Transdifferentiation - Stem Cells, Fatty Muscles and the Role of D3 - Image 1

Intro

Some of tomorrow’s biomedical practices are hidden in today’s overwhelming focus on understanding the underlying processes that would allow for safe and feasible implementations (the dirty work). If this sounds too abstract, let me try to be more specific.

One hot area of research is genetic engineering, whether it has to do with transgenic studies, gene manipulation, gene therapies, epigenetics, and so on. To be even more specific, let’s concentrate on tissue engineering and transdifferentiation.

Trans-what?

Transdifferentiation, according to current theories and experiments, is the irreversible switch of a differentiated cell type to another. It basically occurs when once cell type converts to another, as a result of subtle change in the programme of gene expression [1]. It is a subtype of the processes involving metaplasia when the stem cells of a particular tissue switch to completely different stem cells. See the top image.

Successful transdifferentiation strategies could become useful in cell therapy and regenerative medicine. Since there is great shortage for transplantation of different tissues and organs (and many come with increased risks – ex: graph rejection), this type of strategy would be a cornerstone for cultured tissues and organs (with potentially reduced risks).

Think about the alleviation it could bring to Parkinson’s patients or people suffering from Type 1 Diabetes.

Even though invertebrate species have an increased potential to show transdifferentiation, fewer examples of this process are seen in vertebrates. However, there have been a couple of very well conducted studies in vertebrates. It’s important to understand the mechanics of the process so that we are able to advance in developing efficient strategies to target human diseases. To give you some examples from both worlds:

– in newts (aquatic amphibians), epithelial cells of the iris can form the lens of the eye.
– appearance of hepatic foci (nodules – with potentially negative outcome) in the pancreas (usually occurring in the liver) [4].
– how intestinal tissue can develop at the end of esophagus
– how muscle and neurons can form from neural precursor cells
– how muscle precursor cells can turn into adipose cells
– how pancreatic cells can turn into hepatic cells (hepatocytes)
– and many others.

For a better understanding of the topic, let me briefly introduce stem cells. They are undifferentiated (non-specific) cells that can self-renew (divide) [5] and/or differentiate (become specific) based on environmental stimuli.

There are two known types of stem cells: embryonic and adult (or tissue specific). Embryonic stem cells form from blastocysts (in humans during embryogenesis they arise from the morula in the uterus).

Transdifferentiation - Stem Cells, Fatty Muscles and the Role of D3 - Image 4

Early development of the embryo from ovulation through implantation in humans. The blastocyst stage occurs between 5 and 8-9 days following conception. [10]

Embryonic stem cells are pluripotent and can give rise to many different types of cells.

Conversely, adult stem cells (tissue specific) have a narrower ability to differentiate. For example, hematopoietic stem cells can differentiate in all cell types of the blood and the immune system, but (so far) there has not been observed any capability of them to differentiate into other types of cells from different tissues.

A particular, and very interesting, type of adult stem cells is the bone marrow stem cell. It is sort-of “in-between” embryonic and adult (tissue specific cells) when it comes to its potency of differentiation because it can convert to pancreas, kidney, liver, and lung cells.

While embryonic stem cell strategies raise many ethical questions, a good direction of research would be to focus on discovering more pathways in which adult stem cells can differentiate.

Perhaps bone marrow stem cells could differentiate even into more types of cells. Perhaps tissue specific cells could de-differentiate and convert to cells from other tissues. I have read a study of fat cells de-differentiating, becoming pluripotent, migrating into different locations and differentiating as muscle cells. This may seem far-out to the usual reader and until further studies are conducted, I will not reference to this particular research.

Pancreas and Liver Regeneration

Liver and pancreas regeneration is a field of research that’s been well documented in the last decade. To illustrate, Sarvetnick and Gu (1992) show how after removing 90% of the pancreas in rats, the process of regeneration involves recruiting stem cells from the ductal system along with the proliferation of pancreatic acinar cells (functional units of exocrine pancreas) [6].

They basically used genetically modified mice that have been engineered so that higher levels of inflammation would destroy their beta-cells, mimicking a Type 1 Diabetes context.

In another study, researchers showed how under the action of Dexamethasone (a synthetic glucocorticoid) AR42J, a pancreatic tumor cell line, can be converted to hepatocytes [7].

Transdifferentiation - Stem Cells, Fatty Muscles and the Role of D3 - Image 2

As Shen and colleagues (2004) conclude, “one future possibility is to identify genes that will, for example, convert in a single step bone marrow to cardiomyocytes or pancreatic β-cells” [1].

Vitamin D3 and Intramuscular Fat

Muscle biopsies can show fat infiltrations, which is a potential sign of vitamin D3 deficiency. It’s not quite clear where this fat comes from but a possible explanation is that it is formed from myogenic precursor cells which transdifferentiate into adipocytes.

Ryan et al. (2013) conducted a study where 1,25(OH)2D3 (the active form of vitamin D3) was added in different concentrations in cell cultures of C2C12 (mouse myoblast cell line) for 6 days. They measured markers of fat and muscle development [3].

They used two media: myogenic and adipogenic. The myogenic medium promotes the formation of muscle tissue while the adipogenic medium promotes the formation of fat tissue. Basically, they’ve put C2C12 cells in these two environments and they supplemented each of the 6 cultures (dishes) with different concentrations of 1,25(OH)2D3 (0, 10-13, 10-11, 10-9, 10-7, 10-5 M)

According to the researchers, mature myofibers were formed in both adipogenic and myogenic media but fat droplets were only observed in adipogenic media. Lower concentrations of D3 (10-13, 10-11 M) given to the cells in the adipogenic media showed increased fat accumulation, while very high concentrations of D3 (10-7, 10-5 M) showed inhibition of fat accumulation.

Transdifferentiation - Stem Cells, Fatty Muscles and the Role of D3 - Image 3

It is important to be aware of the fact that infiltration of fat within the muscle tissue may lead to deterioration in muscle strength and functionality [8]. I would give serious consideration when adopting a protocol to build muscle mass and I would be against the general bulking seen in folks who gain mass quickly (gain bodyfat and muscle and the try to lose fat). The quality of the muscle mass may not be as good compared to more considerate approaches. Appropriate sun exposure or supplementation with D3 (25(OH)D) may help but it should be taken as damping tool.

In the same line:

“Certainly for our ancestors, a significant quantity of VitD was primarily obtained from exposure to u.v./sunlight, which induces the conversion of 7-dehydrocholesterol to VitD3. Low levels of VitD in the body, which possibly occur during periods of low u.v. exposure such as winter (Moosgaardet al. 2005, Aguiari et al. 2008), may act as an important regulatory cue in inducing muscle precursor cells to form adipocytes rather than myofibres and enable extra fat depots to be stored in the body during periods of austerity. This speculative hypothesis needs testing in an appropriate animal model.”[3]

Being the first study to demonstrate dose dependent effect of active D3 on the transdifferentiation of muscle into adipose tissue, I see it as a door opener for more studies to come into the field, studies that would be easier to extrapolate and from which useful conclusions and strategies would help improve the human condition [3].

Concluding Thoughts

What is to come seems extremely exciting (at least to me). Yet we have to be aware of the immense power that technology can give to us. It is a double edge sword and if not used properly or if it falls in bad hands it could spell into disaster. But I don’t wanna end in a negative fashion. So, here’s a fascinating video on how transdifferentiation occurs [9]:

The video shows a culture of B cells labeled with green fluorescent protein (GFP) surrounded by red fluorescent yeast (Candida albicans). As the transcription factor C/EBPa is activated within the B cells these aggregate and turn into macrophages that ingest the yeast, so that 51 hours after activation all pathogens became eaten. Credits: Jose Luis Sardina, Francesca Rapino and Timo Zimmermann. [9]

Resources

1. Shen, C. N., Burke, Z. D., & Tosh, D. (2004). Transdifferentiation, metaplasia and tissue regeneration. Organogenesis, 1(2), 36.

2. Eguizabal, C., Montserrat, N., Veiga, A., & Belmonte, J. C. I. (2013, January). Dedifferentiation, transdifferentiation, and reprogramming: future directions in regenerative medicine. In Seminars in reproductive medicine (Vol. 31, No. 01, pp. 082-094). Thieme Medical Publishers.

3. Ryan, K. J., Daniel, Z. C., Craggs, L. J., Parr, T., & Brameld, J. M. (2013). Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells. Journal of Endocrinology, 217(1), 45-58.

4. Lelbach, W. K., Müller, T. R., Kersjes, W., Hartlapp, J. H., & Doss, M. (1989). Multiple nodular foci in the liver associated with chronic hepatic porphyria after previous treatment of breast cancer. Klinische Wochenschrift, 67(11), 592-597.

5. Shenghui, H., Nakada, D., & Morrison, S. J. (2009). Mechanisms of stem cell self-renewal. Annual Review of Cell and Developmental, 25, 377-406.

6. Sarvetnick, N. E., & Gu, D. (1992). Regeneration of pancreatic endocrine cells in interferon-gamma transgenic mice. In Pancreatic Islet Cell Regeneration and Growth (pp. 85-93). Springer US.

7. Shen, C. N., Slack, J. M., & Tosh, D. (2000). Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biology, 2(12), 879-887.

8. Goodpaster, B. H., Carlson, C. L., Visser, M., Kelley, D. E., Scherzinger, A., Harris, T. B., … & Newman, A. B. (2001). Attenuation of skeletal muscle and strength in the elderly: The Health ABC Study. Journal of Applied Physiology, 90(6), 2157-2165.

9. Graf, T. (2014). Hematopoietic stem cells, transdifferentiation and reprogramming.

10. “Human Fertilization” by Ttrue12 – Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons

Photos: here, here, here, and here

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