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)
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

 

ResearchBlogging.org

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

 

 

 

ResearchBlogging.org
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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Inspired By Snake Venom

When I remember the 80s, I think of Nena’s 99 Luftballons, Duran Duran’s Wild Boys and ….snake venom. Back in those days, I used to be a typical high school science nerd. My science nerdiness interfered with my ability to socialize with non-nerds and it was characterized by an unnecessary desire to read science books and articles that I did not really understand, just so that I could show off with some fancy science terminology. I did not have much of an audience to impress, because my class-mates usually ignored me. My high school biology teacher, Herr Sperr, was the only one who had the patience to listen to me. One of the science books that I purchased was called “Gehirn und Nervensystem” (i.e. “Brain and Nervous System”), published by Spektrum der Wissenschaft, the German publisher of Scientific American. It was a collection of Scientific American articles in the field of neuroscience that had been translated into German. I was thumbing through it, looking for some new neurobiology idea or expression that I could use to impress Herr Sperr. While browsing the book, I came across the article “Der Nervenwachstumsfaktor” (originally published in Scientific American as “The Nerve-Growth Factor” in 1979) by Rita Levi-Montalcini and Pietro Calissano.

My curiosity was piqued by this article, because I did not realize that nerves had “growth factors” and because one of the authors, Rita Levi-Montalcini, had just won the Nobel Prize in the preceding year. I started reading the article and loved it, reading it over and over again. I liked the article so much, that I did not even try to show off about it and kept the newly discovered inspiration to myself. There are many reasons why I loved the article and I will just mention two of them:

1. Scientific discovery is an exciting journey, starting and ending with unanswered questions

Levi-Montalcini and Calissano started off by describing the state of knowledge and the unanswered questions in the field of developmental neurobiology and neuronal differentiation in the 1940s, when Levi-Montalcini was about to launch her career as a scientist. They commented on how the simple yet brilliant idea to test whether tumors could influence the growth of nerves sparked a whole new field of investigation. They narrated a beautiful story of scientific discovery, from postulating a “nerve growth factor” to actually isolating and sequencing it. Despite all the advances that Levi-Montalcini and her colleagues had made, the article ended with a new mystery, that the role of the nerve growth factor may be much bigger than all the researchers suspected. The nerve growth factor was able to act on cells that were not neurons and it was unclear why this was the case. By hinting at these yet to be defined roles, the article made it clear that so much more work was necessary and I felt that an invitation was being extended to the readers to participate in the future discovery.

2. Scientific tools can harbor surprises and important clues

The article mentioned one important coincidence that helped shape the progress of discovering the sequence of the nerve growth factor. To assess whether the putative nerve growth factor contained nucleic acids, Levi-Montalcini and her colleagues exposed the “soup” that was inducing the growth of nerves to snake venom. The rationale was that snake venom (by the way, the German expression “Schlangengift” sounds even more impressive than the English “snake venom”) would degrade nucleic acids and if the growth enhancing properties disappeared, it would mean that the nerve growth inducing factor contained nucleic acids. It turned out that the snake venom unexpectedly magnified the nerve growth enhancing effects, because the venom contained large quantities of the nerve growth factor itself. This unexpected finding made it much easier for the researchers to sequence the nerve growth factor, because the snake venom now provided access to a large source of the nerve growth factor and it resulted in a new mystery: Why would snake venom contain a nerve growth factor?

In the subsequent decades, as I embarked on my own career as a scientist, I often thought about this article that I read back in high school. It inspired me to become a cell biologist and many of the projects in my laboratory today focus on the effects of growth factors on blood vessels and stem cells. The article also made me think about the importance of continuously re-evaluating the tools that we use. Sometimes our tools are not as neutral or straight-forward as we think, and this lesson is just as valid today as it was half a century ago. For example, a recent paper in Cell found that the virus used for reprogramming adult cells into stem cells is not merely a tool that allows entry of the reprogramming factors, as was previously thought. The virus tool can actually activate the stem cell reprogramming itself, reminiscent of how the “snake venom” tool was able to induce nerve growth.

Rita Levi-Montalcini was one of the world’s greatest biologists and passed away on December 30, 2012. In addition to her outstanding scientific work, she was also a shining example of an activist scientist with a conscience, who fought for education and research. I never had the opportunity to meet her in person, but I was inspired by her work and I will always see her as a role model.

Image credit: Cover of the book “Gehirn und Nervensystem” by Spektrum der Wissenschaft