Untreated lymphatic swelling promotes weight gain by altering stem cell behaviour

An interesting study of breast cancer related lymphedema suggest that stem cells present in chronically swollen arms exhibit an enhanced ability to form fat tissue, an observation which may explain the dramatic rise in arm fat levels observed in cases of chronic lymphedema.

Fat accumulation is a poorly understood and little discussed side effect of non-pitting lymphedema, an advanced stage of lymphedema where areas of swelling become firm and/or fibrotic.  A recent study examining the tissue composition of women with non-pitting lymphedema reported a 73% increase in adipose (fat) tissue by volume in the lymphedematous arm compared with the unaffected arm, a 47% increase in muscle, and 7% increase in bone (ref 1).  The conservative management of lymphedema through manual lymphatic drainage, compression bandaging and other techniques known collectively as combined (complex) decongestive therapy, is incapable of directly addressing the adipose component of a swollen limb.  Consequently there has been an increased interest in using liposuction to remove the excess fat before employing decongestive therapy, in order to elicit a more complete reduction of limb volume.

Understanding why chronic edema transitions from lymph fluid to subcutaneous fat can inform strategies to prevent the transition, and may eventually enable novel therapies.

In 2013 researchers examined the hypothesis that fat accumulation in advanced lymphedema is an active process that is caused by changes in the behaviour of stem cells normally found in the arm (called “adipose-derived stem cells”), which have the ability to form new fat, bone, muscle, cartilage, tendon and connective tissue (ref 2).  These cells are believed to normally play a role in weight gain and injury repair.  To test this hypothesis the researchers collected hundreds of stem cells from arms with non-pitting (more advanced, or chronic) lymphedema and compared them with stem cells taken from normal arms.  To identify differences in the cells the researchers looked for changes in gene activity (using single-cell transcriptional profiling that can show which genes are active, and hence how cells are behaving) and also tested the functional abilities of these stem cells by seeing what types of tissue they could coax the cells into forming.

The researchers found that stem cells from arms with lymphedema were more likely to form fat (see Figure 1 for an example of their observations), less likely to form vascular tissue including veins and arteries, and may also have an enhanced ability to form new lymphatic tissue.  The latter phenomenon may reflect a compensatory mechanism to help relieve lymphatic pressure, albeit one that is insufficient to overcome the functional deficit arising from lymph node removal. These results may explain the accumulation of adipose tissue observed in chronic lymphedema.

Figure1: Stem cells taken from arms with lymphedema (“Lymphedema hASC”) and treated with factors that promote fat development show increased “oil red O” lipid staining (fat cell formation) compared with stem cells taken from normal arms (“Control hASC”) and treated identically (ref 2).

So what does this mean for patients with lymphedema or for those at risk?

The apparent involvement of stem cells in lymphedema progression (in particular during late stage fat deposition) suggests that progression is an active process driven primarily by cellular changes rather than simply a passive process of lymphatic tissue degradation and a resulting accumulation of fluid, proteins and fats.  Active processes tend to be accelerative in nature (occur with increasing speed as a result of positive feedback), and tenacious.  This explains the need for extreme measures such as liposuction in some cases. Liposuction has been shown in some cases to be able to completely remove all excess tissue volume in advanced (stage 3) cases of lymphedema where the swelling is entirely dominated by the presence of fat. This procedure, while not curative, gives the patient an opportunity to start over, and with appropriate management should be able to avoid re-progression. (See “Patient Guide: Liposuction for Lymphedema“)

Unfortunately, the gradual accumulation of subcutaneous fat in lymphedematous limbs would be expected to cause a gradual loss of the effectiveness of combined decongestive therapy to reduce overall limb volume – a phenomenon we have observed in practice.  In support of this, a recent study showed that combined decongestive therapy is more effective at reducing relative limb volume in mild or moderate cases of lymphedema compared with more advanced cases (see our blog post).  This understanding of disease progression should provide further motivation for patients at risk of developing lymphedema to learn preventative measures and seek therapy in the early stages of the disease when conservative treatment is most effective.

Fat metabolism also slows when lymphatic drainage weakens

To further complicate things, new data suggests that weakened lymphatic drainage can encourage the body to store fat even before noticeable swelling is present. This means that not only does advanced lymphedema promote abnormal fat accumulation, but early sub-clinical lymphatic drainage deficiency can promote the storage of fat. The study in question demonstrated that weakened lymphatic drainage can cause microenvironmental changes in the afflicted tissue that can discourage adipose tissue (fat tissue) to convert stored fat into energy, either while at rest or in response to stimulation (such as exercise). Since fat will in turn exacerbate lymphedema (and morbid obesity cause lymphedema), this finding reinforces the notion that fat and weakened lymphatic drainage can form a vicious feedback loop where one begets the other. This further emphasizes the importance of both good lymphedema self-management practices and good body weight management.

References

1. Brorson H., Ohlin K., et al. Breast cancer-related chronic arm lymphedema is associated with excess adipose and muscle tissue. Lymphat Res Biol. 2009; 7(1):3-10.
2. Levi B., Glotzbach J.P., et al. Molecular analysis and differentiation capacity of adipose-derived stem cells from lymphedema tissue. Plast Reconstr Surg. 2013 Sep:132(3):580-9.