Obesity and Stem Cells - Part II, Bone Marrow
As we saw in Obesity and Stem Cells, Part I, the impact of obesity could be variable depending upon the source of the stem cells. In this particular blog, we will focus upon haematopoietic stem and progenitor cells (HSPCs) in the bone marrow. For this, we are reviewing the paper by van den Berg, et al (2016). Despite the previous blog showing that marrow cells change differently than subcutaneous fat and infrapatellar fat pad cells, Wu et al (2013) only investigated the medicinal signaling cell (MSC) component of the bone marrow cells. van den Berg and colleagues studied cells in greater concentration and a bigger role in bone marrow and, due to the generation of immune cells from HSPCs, a huge role in immune function.
The initial focus upon cells of the bone marrow relates to the importance of the bone marrow as both a stem cell reservoir but also because of the importance of the bone marrow for the immune system. We have already seen that obesity is marked by a chronic, low-grade inflammation (Obesity and Stem Cells, Part I); it is also marked by leukocytosis (increased white blood cell count; this is associated with infection and bone tumors) as well as inflamed adipose tissue. Moreover, we know that continuous activation of the immune system is a stressor for bone marrow HSPCs and that the bone marrow is the primary site for immune cell production. As such, obesity is a stressor for bone marrow HSPCs, and this has significant implications for those with obesity as they struggle with increased illnesses and decreased tissue healing and repair. In Obesity and Stem Cells, Part I, we saw the impact obesity can have on bone marrow-derived mesenchymal stem/stromal cells, or more properly, medicinal signaling cells (MSCs). Today, we focus on HSPCs. While much focus has been placed on MSCs in previous decades, we now know that haematopoietic stem cells (HSCs), not MSCs, are the most osteopoietic cell in the body (Hoffman et al, 2013). In fact, HSPCs are the drivers of tissue regeneration (Dominici et al, 2004). However, this should not be interpreted as meaning that only HSPCs are important. The heterogeneity of cells and signals are crucially important (Marx and Harrell, 2012). Nevertheless, the importance of obesity’s negative impact on HSPCs cannot be ignored.
This paper focused on the population dynamics of HSPCs in relationship to obesity. When diet-induced obesity is caused in mice, there is a significant decrease in proliferation of lineage-Sca-1+c-Kit+ (LSK) cells. Additionally, within the LSK group, there was a shift that occurred as a result of obesity from stem cells capable of self-renewing, to becoming more mature, and shorter living, progenitor cells. Moreover, when testing bone marrow transplantation from obese mice, the results demonstrated impaired multilineage reconstitution. In other words, obesity negatively impacts bone marrow stem cells, and this negative impact includes negative impacts on both bone marrow/stem cell transplantation as well as proper functioning of the immune system. Finally, the results of this study are incredibly important when it is remembered that the authors had mice on a very mild obesogenic diet. In other words, these were not morbidly obese mice, but the results are dramatic enough to demonstrate that even this mild change is clinically significant in terms of how much is negatively impacts bone marrow cells, not just bone marrow stem cells.
Obesity has such a major impact, not only on the complete organism, but also on cells making up the organism. In peripheral blood, obesity leads to an increase in pro-inflammatory immune cells (e.g., granulocytes, CD8+ cytotoxic T cells) - remember, obesity is characterized by chronic inflammation - obesity also leads to a decrease in CD4+ T-helper cells. The total blood leukocyte (TBL) between obese/non-obese groups did not reveal changes immediately upon mice being placed upon a mild obesogenic diet. Rather, the changes took place four weeks after the development of obesity. The TBL also revealed that both the myeloid and lymphoid fractions marked for pro-inflammatory. The increase in Gr1high monocytes and cytotoxic CD8+ T cells (the T cell line is considered to induce adipose tissue inflammation as well as insulin resistance).
Within the bone marrow, the LSK cells are switched out of a quiescent (and long-term surviving) phase into a differentiation (and maturing) phase. Like the TBL changes, the changes in the bone marrow were observed starting at a month post-obesity, rather than due to the change in diet. Within the more mature cells, progenitors, the early multipotent progenitors (E-MPPs) incensed within a few days of obesity and then remained elevated; late multipotent progenitors (L-MPPs) decreased at 10 weeks post-obesity. The increase in lymphoid, myeloid, and monocytes (granulocytes showed no significant difference) in the marrow space is due to the fact that obesity transforms immature stem cells to more mature cells.
LSK cellular maturation in the bone marrow leads to a significant decrease in LK (Lin-c-KIT+) from 4 weeks and LS (Lin-Sca-1+) from 18 weeks after the development of obesity. Common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs) significantly decrease from 18 and 10 weeks, respectively, after the development of obesity.
Finally, the increase in differentiation potential of HSPCs and the decrease in the proliferation capacity of LK and LS cells (significant cellular reduction) compounds the changes already noted. The decrease in proliferation was slightly lower than the decrease in cells (e.g., LSK decreased by 29% and proliferation decreased by 25%); LK cells decreased 52% (with a 37% proliferation decrease) and LS cells decreased 23% (with a 2.5% proliferation decrease). In other words, the dramatic reduction in HSPCs is exacerbated by proliferation decrease, but proliferation decrease alone does not account for the decrease in cellularity.
The relationship of lowering glucose in Type 2 diabetes has been shown to have no correction of leukocytosis; therefore, hyperglycemia itself is NOT the driver of leukocyte production (Nagareddy et al, 2014). Therefore, by observing the cellular changes of obesity, it is now clear why Type 2 diabetes and chronic inflammation result from obesity. These results were also seen in the spleen of the mice, not just the bone marrow.
The decrease in bone marrow HSCs due to obesity has a massive impact that cannot be ignored. The reduction in multilineage reconstitution stimulates differentiation (maturation) and leads to a decrease in the HSPC population. That is, obesity is marked not only by a change in haematopoietic stem cell function, but the reduction in stem cell population means that the immune system of those with obesity is abnormal and as such, obesity, hampers proper immune functioning. The effects of this are only beginning to be understood, but it is clear that the population of immune cells are changed, reduced stem cell population means that the bone marrow haematopoietic stem cell population is overly taxed to produce sufficient blood cells, but also means that this same cell population that is crucial for tissue regeneration is also overly taxed to deal with acute and chronic trauma and disease.
The cellular switch that occurred due to obesity was one in which cells capable of self-renewal (one of the hallmarks of stem cells) toward immune progenitors incapable of self-renewing. Moreover, in obesity, long-term cell-intrinsic alterations in HSPCs occur so that these cells no longer function properly, but also those negative impacts may occur even after weight loss. Consequently, obesity, is even more dangerous than we have thought.
In the next blog, we will look specifically at impact of obesity in the production of blood cells (haematopoiesis) and the entire bone marrow niche.
van den Berg, SM, et al. (2016). Diet-induced obesity in mice diminishes hematopoietic stem and progenitor cells in the bone marrow. The FASEB Journal; 30:1779-88.
Marx, RE and Harrell, DB. (2012). Translational research: The CD34+ cell is crucial for large-volume bone regeneration from the milieu of bone marrow progenitor cells in craniomandibular reconstruction. Oral Caniofac Tissue Eng; 2:263-71.
Dominici, M, et al. (2004). Hematopoietic cells and osteoblasts are derived from a common marrow progenitor after bone marrow transplantation. Proc Natl Acad Sci USA; 101:11761-6.
Hofmann, TJ, et al. (2013). Transplanted murine long-term repopulating hematopoietic stem cells can differentiate to osteoblasts in the marrow stem cell niche. Mol Ther. doi:10.1038/mt.2013.36.
Nagareddy, PR, et al. (2014). Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab; 19:821-35.