Obesity and Stem Cells - Part I, General Overview and Mesenchymal Stem/Stromal Cells (aka, Medicinal
Obesity is never a fun topic to discuss. In fact, even the discussion of the topic can be associated with "fat shaming." However, ignoring the realities of the effects of obesity is more shameful. Moreover, obesity has a special, and difficult, meaning for me personally - I have been obese. I had been very athletic and then was injured. Athletes often struggle with weight gain once they stop competing. Naturally, obesity and its comorbidities have been of interest to me because of my own journey from athlete to obese and to return of the athlete. Over the next few blog posts I will briefly examine the effects of obesity on stem cells - pool size, differentiation potential, function, and more.
I'm certain that everyone reading this blog post is well aware of the dangers and complexities associated with obesity. The Centers for Disease Control and Prevention (CDC) states that individuals with obesity have influences of both behaviors (e.g., dietary patterns, physical activity/inactivity, medications) and genetics to can be contributing factors. For example, common comorbidities of obesity include: osteoarthritis, sleep apnea, high blood pressure, high cholesterol, Type 2 diabetes, venous stasis disease, soft tissue infections, increased body pain, reduced quality of life, poorer mental health outcomes, and is associated with leading causes of death (e.g., diabetes, stroke, heart disease, and some cancers) and these medical care costs in the United States are extraordinarily high; in 2008 it was estimated at $147 billion.1
What remains less well known to clinicians and the public is the negative impact obesity has upon stem cells. Given that I am a researcher and scientist focused upon translating basic science into the practice of regenerative medicine, I started thinking about the impact obesity has on cells with high regenerative potential - cells like stem and progenitor cells. It has been both shocking and motivating to work hard on weight-loss and increase fitness. This loss of weight needs to be done in a methodical manner also; it's not enough to simply lose weight and not exercise or grow muscle (in a future blog post on obesity and stem cells we will delve into exercise and stem cells in more detail). Fat in muscle and in bone marrow also hampers the body, the ability to fight infections, and regenerative cells.
Simply, obesity is brutal on the body, including stem, progenitor, and terminally differentiated cells. Not only does obesity negatively change the cellular dynamics (ratio of cell types) with the bone marrow (the major stem cell reservoir), obesity can also lead to exhaustion of stem and progenitor cells. In other words, not only do the stem cells differentiate (that is, they mature and lose their "stemness" properties) more quickly, the stem cell population also loses the ability to replace themselves appropriately. That is a powerful knockout combination! These cells are crucial for helping the body repair itself and for the demands of the body just to keep alive. Obesity harms the cells and the immune system (bone marrow is where immune cells are matured).
Obesity also causes the body to be in a constant state of low-grade inflammation. That means, that the bodies of those with obesity are constantly exhausting themselves trying to deal with inflammation. Cells respond to signals in their environment. In obesity, cells are met with numerous signals that tell them they are in an inflammatory state. What this means is that the body is stressed by having obesity. While the natural means of overcoming stressors is through an inflammatory process, in obesity, the inflammation does not stop and the body doesn't heal properly.
This blog post is the start of a mini-series of blog posts on stem cells and obesity. Stem cells, are best generically defined as being able to produce clonogenic entities (clones, exact copies) as well as asymmetric division (a more differentiated, or more mature, cell). Anything that harms stem cells will necessarily harm humans, which is why one interesting avenue of research involving stem cells is for drug toxicity studies. The pool of stem cells in the body is small, that is, they are very rare cells. Additionally, stem cells also play key roles in homeostasis as well as in tissue regeneration and repair following injury or even simply cell replacement (e.g., blood cell replacement). Therefore, understanding the impact of this common medical presentation is important for clinicians, patients, researchers investigating effectiveness of autologous (donor and recipient are the same person) cellular therapies, as well as in the development of practice guidelines - perhaps not all patients are candidates for such treatments. There has been a rise in physicians being unwilling to treat active smokers with these, and many other types of, therapeutic tools because of the negative impact smoking has on outcomes. It may be that morbid obesity may also be of such a strong negative impact. Over the next few blogs, we will highlight some research findings relating to stem cells and obesity.
This blog will focus on the negative impact of diet-induced obesity on stem cell differentiation potential. "This study is significant for the development of autologous stem cell therapy for obese patients as obesity is highly prevalent in the US and continuously increasing in other countries."2 One of the striking elements of obesity is that it is characterized by chronic low-grade system inflammation. This chronic inflammation is associated with both osteoarthritis, as the CDC reported and was referenced above, as well as impaired tissue healing.3 Impaired tissue healing is striking because that intimates that obesity could negatively impact stem cells that are active in tissue healing. Moreover, it is now known that two types of macrophages exist (M1 is inflammatory and catabolic whereas M2 is anti-inflammatory and anabolic); in obese individuals, the M2 phenotype macrophages switch to M1 phenotype and increase inflammatory levels. This shift may be extremely important in driving the systemic inflammation as well as potentially inhibiting tissue repair.
This particular study by Wu et al (2013) investigated three sources of stem cells from mice - bone marrow, adipose tissue, and infrapatellar fat pad and compared such cells from both lean and diet-induced obese mice. "The study's findings support the hypothesis that obesity alters the properties of adult stem cells in a manner that depends on the cell source." Unfortunately, the mechanisms by which obesity alters cell function are not fully understood and may involve chronic exposure to free fatty acids, but may also involve other obesity-associated cytokines. Wu et al investigated “mesenchymal stem cells” (MSCs, also known as mesenchymal stromal cells); however, it is best to think of MSCs as perhaps a progenitor, but not a stem cell. In fact, Dr. Arnold Caplan, who coined the term “mesenchymal stem cell” in 1987 now refers to these cells as “medicinal signaling cells” and also argues that there is a lack of in vivo data to demonstrate that these cells behave as stem cells.4,5 Rather, MSCs can be coaxed in a laboratory down the three layers of the mesenchyme as a result of in vitro artifact and in vivo their role is focused on secreting trophic factors.
Obesity definitely led to alterations in cellular density, function, and differentiation capacities. Moreover, obesity had different impacts based upon cell source location (Table 1). While there was a trend for an increased prevalence in MSCs and sqASCs, the decrease in chondrogenic potential associated with obesity is a more significant finding and it appears that bone marrow-derived stem cells have a more universal negative impact from obesity than do cells from subcutaneous and infrapatellar fat pad sources. In other words, obesity alters the properties of adult stem cells but the impact of obesity is also source dependent. Consistently, the chondrogenic potential of cells from obese mice is decreased compared to the chondrogenic potential of cells from lean mice.
In future blogs we will continue to the examine the impact of obesity and then the final blog on obesity and stem cells will put everything together in summary fashion. For today, just allow the concept of obesity leading to changes in cellular function to percolate.
TABLE 1. Differences in stem cell function in obese mice compared to lean mice and cell source location differences.
1. Centers for Disease Control and Prevention. Overweight & Obesity. https://www.cdc.gov/obesity/adult/causes.html Accessed Feb 2, 2018.
2. Wu, CL; et al. (2013). Diet-induced obesity alters the differentiation potential of stem cell isolated from bone marrow, adipose tissue, and infrapatellar fat pad: The effects of free fatty acids. Int J Obes (Lond); 37:1079-1087.
3. Kuo, JH; et al. (2011). Renal transplant wound complications in the modern era of obesity. J Surg Res; 173:216-223.
4. Caplan, AI. (1987). Bone development and repair. Bioessays; 6:171-5.
5. Caplan, AI. (2010). What’s in a name? Tissue Engineering: Part A; 16:2415-7.