In this series on the impact of obesity upon stem cells, we have reviewed a bit of data on stem cells (and/or progenitor cells) from various sources and seen that the impact in terms of the numbers of cells and the cellular functions are influenced by obesity as well as cell source. Additionally, we have seen that there are long-term consequences of obesity and there may be some irreversible damage caused by obesity. Some of these long-term consequences involve haematopoiesis (generation of blood cells) which we know to be crucially important to survival and proper functioning of the immune system. Therefore, today’s blog will be focused specifically on haematopoiesis and the bone marrow niche, as a way of completing the story of the bone marrow cellular concentration changes and the loss of self-renewal abilities due to obesity. Today’s blog is focused on a paper by Adler et al (2014). We continued with the discussion on obesity because it is a massive global pandemic and rarely do topics such as cellular function, cellular dynamics, immunity, stem cell activity, and others enter into the discussion on the dangers of obesity. Moreover, the clinician must make ethical decisions about how to treat those with obesity. For example, numerous physicians (e.g., pulmonologists) have developed rules for what treatments will be offered to those that smoke and what treatments are reserved until after smoking cessation. If autologous cellular therapies do not function appropriately in patients that are obese, such patients should be counseled to pursue alternate treatment options. Finally, it is hoped that those with obesity may glean valuable information from these posts that can be used as discussion points with their physicians and perhaps provide additional incentive to increase exercise and lose weight.
We have seen that obesity increases the susceptibility to numerous diseases as well as the role obesity plays in undermining the viability and fate selection of haematopoietic stem cells (HSCs); Obesity and Stem Cells, Pt II briefly outlined changes in the bone marrow microenvironment that disrupts the numbers and lineage fates of blood cells progenitors. Obesity and Stem Cells, Pt I demonstrated that obesity causes increases in size and numbers of adipocytes in the bone marrow space. These changes disturb HSC interactions with neighboring cells (e.g., osteoblasts, osteoclasts, medicinal signaling cells (MSCs), endothelial progenitor cells, and others).
This review paper is focused upon four areas:
Structure and function of the haematopoietic system - HSC development and differentiation
Heterogenous regulatory environment of the bone marrow (regulate HSCs)
Adipocytes and adipose tissue - health and obesity
Effect of obesity on bone marrow niche, haematopoiesis, and immunity.
1. Haematopoietic system and HSCs
Traditionally, two lines were used to describe hematopoiesis (process by which all the blood cells are produced) - myeloid and lymphoid lineages.The immune system has two separate branches - innate immunity and adaptive immunity. With few exceptions, myeloid cells are critical to innate immunity while lymphoid cells are critical to adaptive immunity. Innate immunity allows for a rapid defense against pathogens due to injury or disease. Innate immunity is not specific to one type of pathogen; rather, innate immunity targets what is considered foreign elements rather than host; however, prolonged activation of innate immunity can lead to tissue destruction. Alternatively, adaptive immunity has a very specific target. The downside of adaptive immunity is that it costs time to build an immune response to a specific pathogen. Subsequent infections from the same pathogen does allow for a much quicker and forceful response due to immune memory to the pathogen’s specific antigen. The haematopoietic system, therefore, involves two systems of immunity which are crucial for survival. Interfering with the proper functioning of the immune system is dangerous. Having the knowledge that obesity does negatively interfere with the immune system, should make each of us further develop in our understanding of the dangers of obesity.
We continue to functionally defined HSCs as cells that are capable of rescuing lethally irradiated animals and “restoring stable, long-term and full-spectrum haematopoiesis” (p. 738). However, as we have seen, in brief, obesity hampers HSCs from being able to function properly, and as we saw in Obesity and Stem Cells, Parts I and II, obesity also limited the efficacy of HSC/bone marrow transplantation. “Ultimately, the relationship between the bone marrow and the haematopoietic populations is dependent on the composition of the bone marrow. Consequently, changes to the bone marrow phenotypes, such as those that occur with increased adiposity, inevitably affect haematopoietic maintenance and differentiation, ultimately putting immune function at risk. Therefore, the very reason the HSC is called an HSC no longer behaves properly because of obesity should be an enormous warning sign of impending danger.
2. Heterogenous regulatory activity in marrow environment
The bone marrow is the primary site of haematopoiesis in adults and while haematopoiesis is an essential function of HSCs, it is not the only function of HSCs. As we saw in Obesity and Stem Cells, Part II, HSCs and HSPCs are the drivers of tissue regeneration (a second essential function) and work cooperatively with MSCs to change the microenvironment from one of tissue destruction to one marked by tissue repair and regeneration. Nevertheless, the primary essential function of HSCs is haematopoiesis. If seen as just by numbers, the body replaces about 100 million red blood cells, every minute, not to mention the white blood cells and platelets (megakaryocytes). In other words, keeping the bone marrow intact and functioning properly is crucial to the body’s immunity and blood. Haematopoiesis is a complex event and the bone marrow microenvironment provides a “critical regulatory milieu that is responsible… for orchestrating the differentiation of HSCs into the different types of mature blood cells” (p. 739).
As has been mentioned over the past few blog posts, MSCs and HSCs cooperate. In fact, many of the factors secreted by MSCs are specific to the survival of HSCs. As an example, Kit ligand (also known as Stem Cell Factor, SCF) is a cytokine that has an essential and non-redundant role and is produced by marrow MSCs. Kit ligand binds to the specific receptor on the cell surface of HSCs and stimulates intracellular kinase activity that leads to activation of pathways involved in cell survival and differentiation. In a future blog, we will analyze how blood, bone marrow, and bone are all connected and should be thought of as a functional unit rather than independent subunits; as an example, some bone disorders are actually blood disorders that manifest in the bone because of changes in haematopoiesis. In fact, in obesity, it is readily observed that there is an increase of osteoporosis, at least, in part due to adiposity of bone marrow and disrupted haematopoiesis and osteopoiesis.
While MSCs do not directly produce blood cells, they do have a role in haematopoiesis. That is, MSCs express many factors that establish the haematopoietic stem cell niche; MSCs express CXCL12 (also referred to as stromal-derived factor 1-alpha, SDF-1α). CXCL12 is a crucial factor that maintains HSC populations and regulates HSCs. If MSCs are eliminated (for example, through a knockout experiment) there is a severe reduction in the maintenance of HSPCs and HSCs not longer home to the bone marrow properly. As we have seen in Obesity and Stem Cells, Parts I and II, MSCs are important to study when looking at obesity because they serve as the precursors to adipocytes and this adipogenesis is competitive to osteoblastogenesis (development of osteoblasts; osteoblasts build bone). As such, because of obesity-derived adipogenesis, we see loss of bone in obesity. In conditions that favor obesity and Type 2 diabetes, MSCs preferentially differentiate into adipocytes rather than osteoblasts. Therefore, obesity and adipogenesis can reduce the MSC pool needed to support HSCs and therefore, amplify the disruption to the bone marrow and immune functions.
Another element in the bone marrow space along the endosteum are osteoclasts. Osteoclasts are derived from HSPCs and are responsible for resorbing bone matrix during bone remodeling; however, osteoclasts are also involved in the maintenance and fate selection of HSCs. While osteoblast secretion of CXCL12 leads to retention of HSCs, osteoclasts mobilize HSCs by enzymatically cleaving CXCL12, which demonstrates a competitive balance between osteoclasts the cleave CXCL12 and osteoblasts that secrete CXCL12 to bind HSCs through the CXCR4 receptor. Bone marrow inflammation due to obesity favors “osteoclast expansion and activation, leading to bone loss and impaired maintenance of HSCs in the niche” (p. 740). Additionally, osteoclasts function as regulators of haematopoiesis both independently and in cooperation with other niche cells, as demonstrated through extended bisphosphonate treatments. Bone resorption through osteoclastic activity releases high levels of calcium (Ca2+) for HSCs to navigate through the bone marrow and also to lodge in the endosteal bone surface.
3. Adipocytes and adipose tissue - healthy and in obesity
Adipocytes exist in the bone marrow, along with osteoblasts, MSCs, vascular cells, osteoclasts, HSPCs, and other marrow residents, but with age and disease, adipocytes increase size and numbers. White adipocytes (most frequently called adipocytes) are distinguished from brown adipocytes in that white adipocytes specialize in storing energy (in the form of triglycerides) whereas brown adipocytes extract energy from lipids in the form of heat. With prolonged caloric excess, the mass of adipose tissue expands. The fatty tissue then undergoes remodeling to allow for the tissue expansion and removal of dead adipocytes by adipose tissue macrophages, which can contribute to the increased inflammatory profile of adipose tissue in the state of obesity and linked to insulin resistance.
Bone marrow adipocytes seem to be a special class of adipocyte and are a mix of white and brown adipocyte phenotypes, called beige adipocytes. Unfortunately, with aging and metabolic challenges such as Type 2 diabetes, the brown adipose phenotype is lost and creates a shift in the composition of the bone marrow in individuals with obesity. Continued obesity bring these adipocytes to their maximum capacity to store and adipocytes and lipid droplets move to nonadipose tissue areas (e.g., skeletal muscle, liver). Adipocyte invasion of the bone marrow due to obesity disrupts the cellular composition of the bone marrow niche and displace and sever the important connection between HSPCs and niche cells.
4. Obesity, bone marrow niche, haematopoiesis, and immunity
As has been revealed in this and previous blogs, obesity promotes conditions favorable to chronic, systemic health issues that contribute to a significant decrease in life expectancy while also increasing the risk of infections and illnesses, including influenza, nosocomial (hospital-born) and post-surgical infections. Additionally, we have seen that the changes in the immune system due to obesity are derived, at least in part, from alterations in the haematopoietic system. In a study referenced by Adler et al, it was found that 7 months of diet-induced obesity “induced significant trabecular bone loss and B-cell depletion, affecting both immature bone marrow and mature peripheral blood B cells — coupling a damaged bone marrow niche to reduced bone quality and compromised function of the immune system” (p. 742) and when the memory T cells are functionally and maintenance-impaired, there is an increase in mortality from influenza. The link between metabolic health and immunity can be seen by those individuals with obesity that also are so-called metabolically healthy in that such individuals had normal populations of leukocytes rather than the leukocytosis we discussed in Obesity and Stem Cells, Part II. We also now know that adipocytes in the bone marrow affect HSCs under both normal conditions, but also under challenges, such as obesity. Adipocytes actively inhibit HSCs and haematopoietic reconstitution. “Any method that constrains bone marrow adipogenesis is likely to preserve or even increase haematopoietic activity. Interestingly, bone marrow cavities that are highly populated by adipocytes under normal physiological conditions (such as in mouse tail vertebrae) store relatively few and largely quiescent HSCs, indicating that adipocytes do not directly damage HSCs, but fail to support their proliferation” (p. 743). Leukocytosis, as discussed in previous blogs, is secondary to systemic inflammation. Moreover, leukocytosis also contributes to systemic inflammation. Leukocytosis, in those with obesity could be detrimental to a properly functioning immune system.
Exercise must be discussed for its role in limiting bone marrow adipocytes. In addition, “exercise can directly address many of the health consequences of obesity, without first reducing adiposity” (p. 744). Examples of this can be seen in improved cardiac function and reduction in blood pressure, as well as serum markers of liver function and suppress hepatocyte apoptosis before body composition is altered. In other words, the first step in overcoming issues associated with obesity is to safely introduce/increase exercise. Bone marrow adiposity has been shown to be proportionally reduced by high-impact loading regimes, but this was greater in those that were lean rather than in those with obesity. In mice, both lean and obese mice benefitted equally from voluntary use of a running wheel. Growth hormone is released following exercise and is a necessary component in osteoblastic activity and reduced marrow adiposity. Lack of growth hormone, even in the presence of weight reduction, still led to an increase in bone marrow adipocytes. Further support for exercise can be seen that MSCs subjected to subtle mechanical signals move away from adipogenesis to osteoblastogenesis, even in highly adipogenic environments.
As we have also seen, obesity compromises the core haematopoietic system. This leads to increases susceptibility to infectious diseases and catalyses decline in the general health of those with obesity. The implication is that obesity either directly or indirectly compromises immune function. The progression of obesity follows other metabolic disorders (e.g., anorexia, osteoporosis, aging) - bone marrow adiposity and disruption of the haematopoietic microenvironment.
We also saw that exercise is crucially important to overcome the results of obesity and weight loss alone will not resolve all the issues. Losing weight is also important, but exercise will release growth hormone to try to restore bone marrow cellularity and consequently, immune function. Due to the rapid growth of the obesity pandemic, clinicians must be aware of the issues associated with obesity. Specifically, within regenerative medicine, patients with obesity are likely to be seen for increased arthritis and difficulty healing following trauma. Important clinical decisions must be made as to whether or not autologous cellular therapy is a suitable treatment for consideration.
Adler BJ, Kaushansky K, and Rubin, CT. (2014). Obesity-driven disruption of haematopoiesis and the bone marrow niche. Nature Reviews: Endocrinology; 10:737-48.