Does Human Fat Contain Stem Cells?

Aeon Magazine recently published my longform essay on our research with human liposuction samples and our attempts to use fat for regenerative and therapeutic purposes. Many research groups, including our own group, have been able to isolate stem cells from human fat. However, when it came to using this cells for treating cardiovascular disease, the cells behaved in a manner that we had not anticipated.

Undifferentiated mesenchymal stem cells (left) and their fat neighbors (right) – From our PLOS One paper

We were unable to convert them into heart muscle cells or blood vessel endothelial cells, but we found that they could help build large networks of blood vessels by releasing important growth factors. Within a few years of our initial publication, clinical trials with patients with blocked arteries or legs were already being planned, and are currently underway.

We decided to call the cells “adipose stromal cells” because we wanted to emphasize that they were acting as a “stroma” (i.e. supportive environment for blood vessels) and not necessarily as stem cells (i.e. cells that convert from an undifferentiated state into mature cell types). In other contexts, these same cells were indeed able to act like “stem cells”, because they could be converted into bone-forming or cartilage-forming cells, thus showing the enormous versatility and value of the cells that reside within our fat tissues.

The answer to the question “Does Human Fat Contain Stem Cells?” is Yes, but these cells cannot be converted into all desired tissues. Instead, they have important supportive functions that can be used to engineer new blood vessels, which is a critical step in organ engineering.

In addition to describing our scientific work, the essay also mentions the vagaries of research, the frustrations I had as a postdoctoral fellow when my results were not turning out as I had expected, and how some predatory private clinics are already marketing “fat-derived stem cell therapies” to paying customers, even though the clinical results are still rather preliminary.

 

For the readers who want to dig a bit deeper, here are some references and links:

 

1. The original paper by Patricia Zuk and colleagues which described the presence of stem cells in human liposuction fat:

Zuk, P et al (2001) “Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies”

 

2. Our work on how the cells can help grow blood vessels by releasing proteins:

Rehman, J et al (2004) “Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells”

 

3. Preliminary findings from ongoing clinical studies in which heart attack patients receive infusions of fat derived cells into their hearts to improve heart function and blood flow to the heart:

Houtgraf, J et al (2012) “First Experience in Humans Using Adipose Tissue–Derived Regenerative Cells in the Treatment of Patients With ST-Segment Elevation Myocardial Infarction”

 

4. Preliminary results from an ongoing trial using the fat-derived cells in patients with severe blockages of leg arteries:

Bura, A et al (2014) “Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia”

 

5. Example of how “cell therapies” (in this case bone marrow cells) are sometimes marketed as “stem cells” but hardly contain any stem cells:

The Largest Cell Therapy Trial in Heart Attack Patients Uses Hardly Any Stem Cells

 

6. The major scientific society devoted to studying the science of fat and its cells as novel therapies is called International Federation for Adipose Therapeutics and Science (IFATS).

I am not kidding, it is I-FATS!

Explore their website if you want to learn about all the exciting new research with fat derived cells.

 

7. Some of our newer work on how bone marrow mesenchymal stem cells turn into fat cells and what role their metabolism plays during this process:

Zhang, Y et al (2013) “Mitochondrial Respiration Regulates Adipogenic Differentiation of Human Mesenchymal Stem Cells”

 

Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, & Hedrick MH (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue engineering, 7 (2), 211-28 PMID: 11304456

 

 

 

Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, & March KL (2004). Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation, 109 (10), 1292-8 PMID: 14993122

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Using Viagra To Burn Fat

Mammals have two types of fat tissue: Brown Adipose Tissue (BAT or “brown fat”) and White Adipose Tissue (WAT or “white fat”). Brown fat cells are packed with many small fat droplets and mitochondria, which is why they appear “brown” under the microscope. Their mitochondria contain high levels of the protein UCP-1 (uncoupling protein 1), which “uncouples” fat metabolism from the generation of chemical energy molecules (ATP) for the cell. Instead, brown fat cells release the energy contained in the fat in the form of heat. This explains why brown fat is primarily found in hibernating animals or in newborns that need to generate heat. They burn their fat to maintain their body temperature. White fat, on the other hand, cannot be burned off so easily and also seems to responsible for many of the deleterious effects associated with obesity, such as diabetes and inflammation.

Recent studies in humans have shown that even adult humans have small stores of brown fat, primarily located in the neck or near big blood vessels. Occasional small islands of brown fat cells can be found amid the large white fat tissue in the adult. Since brown fat is generally considered to be much healthier than white fat, scientists have tried to develop methods to convert white fat into brown fat. Some have used genetic approaches in mouse models of obesity, others have exposed human subjects to a few hours of cold temperatures. The paper “Increased cGMP promotes healthy expansion and browning of white adipose tissue” published in the FASEB Journal by Michaela Mitschke and colleagues (Online publication January 9, 2013) uses a rather unusual approach to induce the “browning” of white fat.

The researchers treated mice with Viagra (sildenafil), a drug that is normally used for erectile dysfunction. They found that only seven days of Viagra treatment increased the levels of the brown fat protein UCP-1 and that the white fat began showing the presence of “beige” (not quite white and not fully brown) fat. The choice of Viagra was not quite arbitrary, because they also showed that cultured fat cells contain cGMP-dependent protein kinase I (PKGI), which is part of the signaling pathway targeted by Viagra, and that increasing the levels of PKGI converted these cells into thermogenic brown fat cells. The researchers did not observe any weight loss in the mice, but they attributed this to the fact that they purposefully chose a very short treatment time in order to investigate fat conversion in the absence of fat loss. Their data suggests that longer treatment would lead to even more white-to-brown conversion of fat and to an actual weight loss, because the generated “beige” or brown-like fat cells could be easily burned off. A prior study that treated mice for 12 weeks with Viagra did indeed show some evidence of weight loss with Viagra treatment.

This new study is quite interesting and may have important practical implications because it uses an approved drug that is commonly available for human studies. Treating obese patients with Viagra would be much easier than trying to genetically convert their white fat to brown fat or to expose them to long periods of cold. However, overweight people should not expect that “Super-Size” orders at their favorite fast food joint will come with a Viagra pill. They also should not run to their physicians to ask for Viagra prescriptions at this point. One has to bear in mind that there are a number of caveats when trying to apply these findings in mice to humans. Chronic Viagra treatment in humans may be associated with some significant side effects and there is no consensus that “browning” of fat in adult humans will necessarily improve their health. Most of the data on the benefits of creating brown fat are based on animal studies. We therefore still need to await future studies, both in animals and in humans, that study the impact of long-term Viagra treatment on weight loss and associated health benefits as well as potential side effects, before definitive conclusions can be drawn. In the mean time, there will be plenty of opportunities to milk this research finding for humorous quips at late night talk shows.

 

Image credit: Co-culture of pre-adipocytes with mouse endothelial cells, via Wikimedia, Authors: Alexes Daquinag, Glauco Souza

Mitschke, M., Hoffmann, L., Gnad, T., Scholz, D., Kruithoff, K., Mayer, P., Haas, B., Sassmann, A., Pfeifer, A., & Kilic, A. (2013). Increased cGMP promotes healthy expansion and browning of white adipose tissue The FASEB Journal DOI: 10.1096/fj.12-221580