Fasting Improves Recovery of Bone Marrow Stem Cells after Chemotherapy

[Note: This is a guest post by Tauseef (@CellSpell)]

Fasting is defined as either completely abstaining from or minimizing food intake for a defined period time – ranging from about 12 hours to even a few weeks. Calorie restriction, on the other hand, refers to an overall reduction in the daily calorie intake by about 20%-40% without necessarily reducing the meal intake frequency. Although calorie restriction is well-suited for weight loss and thus also reduces the risk of chronic diseases such as diabetes or heart disease, proponents of fasting claim that it has distinct health benefits which cannot be attributed to weight loss.

 

Glass of water by Magalos via Shutterstock
Glass of water by Magalos via Shutterstock

Scientific data for the benefits of fasting have been rather limited, but some recent studies have now shown that fasting can enhance cellular resistance to toxins and increase longevity in laboratory animals as well as humans. Fasting has also been proposed as a therapeutic approach in the setting of selected diseases such as neurodegeneration, seizures and rheumatoid arthritis.

The recent study “Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression” published in the journal Cell Stem Cell by Cheng and colleagues in 2014 investigated a novel benefit of fasting – enhancing recovery from the side effects of treatments. The researchers looked into whether fasting in a mouse model of chemotherapy would help the mice recover from the suppression of their blood cell production. Chemotherapy drugs suppress the growth of malignant cancer cells, but they unfortunately often also affect healthy stem cells and other growing cells needed to maintain our health. The bone marrow contains blood-forming hematopoietic stem cells (HSCs), which churn out billions of healthy blood cells, such as white blood cells (WBCs) and red blood cells (RBCs), every day. When these healthy stem cells are suppressed or even eliminated as a form of collateral damage during chemotherapy, patients can develop severe anemia or immune suppression.

In their study, Cheng and colleagues showed a strong protective role of multiple cycles of fasting (no food for 48 to 120 hours) in mice treated with the chemotherapy drug cyclophosphamide. The fasting was able to partially reverse the suppression of bone marrow stem cells, improve immune function and reduce the death rate of the mice. The researchers found a similar protective effect of fasting in cancer patients (no food for 72 hours) who were treated with anti-cancer drugs as a part of phase I clinical trial, although there was no control group and no details were provided about the overall fluid and calorie intake of the patients.

By utilizing a gene array to screen for the expression levels of thousands of genes, the researchers determined that the benefits of fasting were due to the reduction of insulin-like growth factor-1 (IGF-1) hormone levels in the bone marrow. Suppression of IGF-1 by fasting increased the expansion of bone marrow stem cells (HSCs) and improved the immune function during chemotherapy. Mice in which the IGF-1 gene was deleted showed a similar degree of protection as what was observed in fasting mice.

Although, the present study provides interesting new insights for how fasting can improve bone marrow function in chemotherapy, some unanswered questions need to be addressed in future studies. People who are suffering from cancer routinely lose a substantial amount of weight during the progression of their disease, and it is not clear that their physical health would be able to tolerate the additional stress of fasting. Moreover, the researchers did not provide details about the calorie restriction and potential weight loss associated with the fasting. Perhaps the benefits in the mice were not due to fasting but instead due to calorie restriction. Furthermore, the patient study only showed that 72 hours of fasting increased lymphocyte counts, but did not describe the nutritional status and any potential weight loss in the patients.

This study is one of the first studies to uncover the molecular mechanisms of how fasting can improve the recovery of bone marrow stem cell function after chemotherapy. Despite its limitations, the study also identified the IGF-1 pathway as a potential new target for treatments to enhance bone marrow stem cell recovery. The outcomes of chemotherapy might be therefore improved by pharmacologically suppressing IGF-1 without requiring fasting, but this idea would still need to be tested in humans.

 

– M. Tauseef (@CellSpell)

 

 

ResearchBlogging.org

Cheng, C., Adams, G., Perin, L., Wei, M., Zhou, X., Lam, B., Da Sacco, S., Mirisola, M., Quinn, D., Dorff, T., Kopchick, J., & Longo, V. (2014). Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression Cell Stem Cell, 14 (6), 810-823 DOI: 10.1016/j.stem.2014.04.014

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Turning Off Inflammation: A Novel Anti-Inflammatory Switch in Macrophages

[Note: This is a guest post by Tauseef (@CellSpell), an excellent immunologist and one of my faculty colleagues at the University of Illinois, who is quite excited about science outreach and science blogging.]

Macrophages are important immune cells which regulate inflammation, host defense and also act as a ‘clean-up crew’. They recognize, kill and engulf bacteria as well as cellular debris, which is generated during an acute infection or inflammation. As such, they are present in nearly all tissues of the body, engaging in 24/7 surveillance. Some macrophages in a tissue are derived from circulating blood monocytes which migrate into the tissue and become “phagocytic” – acquire to ability to “eat”. Other macrophage types permanently reside within a tissue such as peritoneal macrophages in the abdomen or microglia in the brain. Macrophages constitute a highly diverse population of cells. For example, their tissue localization determines what genes are turned on in any given macrophage type and how they will function. One of the most important recent developments in macrophage biology and immunology has been the realization that tissue macrophages can be broadly divided into at least two very distinct subsets: M1 and M2.

 

Macrophage and Virus (via Shutterstock)
Macrophage and Virus (via Shutterstock)

Pro-inflammatory M1 macrophages are predominantly involved in digesting bacteria and debris. They release pro-inflammatory molecules which then attract other immune cells and inform them that their assistance in fighting off the infection is sorely needed. M2 macrophages, on the other hand, help resolve inflammation by secreting anti-inflammatory molecules and calming down their M1 cousins. During inflammation, both sets of macrophages are activated but M1 cells appear first and M2 later. This makes sense because it allows the body to first focus on fighting off the injury with its powerful M1 cells, but also prevents excessive damage by subsequently initiating an endogenous brake (M2 cells) to prevent excessive inflammation.

Inadequate activation of M2 cells during infection or inflammation can have disastrous effects. If the pro-inflammatory M1 cells have no anti-inflammatory counterpart, then they will keep on releasing pro-inflammatory molecules. These, in turn, will attract increasing numbers of immune cells and set in motion a vicious cycle of severe inflammation and massive fluid accumulation. If the levels of M1 activity are extremely high, some tissues such as the lung can be flooded with fluid and cells which prevent oxygen supply to the body, and ultimately result in death. Lower levels of persistent M1 cell activity may not lead to death, but could cause a simmering chronic inflammation and autoimmune diseases.

Restoring the balance of M1 and M2 cells, or selectively increasing M2 cells is becoming a hot area in immunology. If it were possible to increase M2 cells by turning on specific molecules or pathways, one could treat autoimmune diseases or prevent exaggerated inflammatory responses. This would be a far more elegant than relying on more conventional immune suppressants such as steroids which could compromise the body’s ability to resist future infections.

A recent paper published in the journal Cell (2014) by Yasutaka Okabe and Ruslan Medzhitov, has identified a transcription factor which is specific for anti-inflammatory macrophages. The researchers used a gene array to screen for over 40,000 genes and found that the transcription factor GATA6 was a key regulator of whether peritoneal (abdominal) macrophages were pro-inflammatory or anti-inflammatory. More importantly, the researchers found that retinoic acid, an active metabolite of Vitamin A, increases the GATA6 levels in macrophages, and thus pushes them towards an anti-inflammatory identity. Genetic deletion of GATA6 or depletion of Vitamin A in the diet of mice resulted in peritoneal macrophages becoming more pro-inflammatory (M1-like).

Although the present study provides an evidence of the role of Vitamin A and its metabolite retinoic acid in the suppression of inflammation by activation of GATA6 in macrophages, some unanswered questions need to be addressed in future studies. The researchers showed that Vitamin A depletion pushes macrophages towards the pro-inflammatory M1-like identity, but the researchers did not try the converse: They did not test whether giving vitamin A to animals would increase anti-inflammatory macrophages. The researchers also did not track the individual macrophages to truly prove that the pro-inflammatory cells were actually converting into anti-inflammatory macrophages versus merely recruiting a pool of anti-inflammatory cells from the blood.

An important lesson that we can take away from this paper is that vitamins and their metabolites are regulators of the immune response. Either too little or too much Vitamin A may be detrimental because its metabolite retinoic acid could upset the finely regulated balance of the immune system. This study is one of the first to unravel the molecular switches which regulate the formation of pro-inflammatory and anti-inflammatory macrophages. We are only at the beginning of this exciting area of research and hopefully, in the years to come, selective manipulation of these switches will allow us to treat acute inflammatory and chronic autoimmune diseases for which few therapies are available.

 

– M. Tauseef (@CellSpell)

 

ResearchBlogging.org

Okabe Y, & Medzhitov R (2014). Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell, 157 (4), 832-44 PMID: 24792964

 

Immune Cells Can Remember Past Lives

The generation of induced pluripotent stem cells (iPSCs) is one of the most fascinating discoveries in the history of stem cell biology. John Gurdon and Shinya Yamanaka received the 2012 Nobel Prize for showing that adult cells could be induced to become embryonic-like stem cells (iPSCs). Many stem cell laboratories now routinely convert skin cells or blood cells from an adult patient into iPSCs. The stem cell properties of the generated iPSCs then allow researchers to convert them into a desired cell type, such as heart cells (cardiomyocytes) or brain cells (neurons), which can then be used for cell-based therapies or for the screening of novel drugs. The initial conversion of adult cells to iPSCs is referred to as “reprogramming” and is thought to represent a form of rejuvenation, because the adult cell appears to lose its adult cell identity and reverts to an immature embryonic-like state. However, we know surprisingly little about the specific mechanisms that allow adult cells to become embryonic-like. For example, how does a blood immune cell such as a lymphocyte lose its lymphocyte characteristics during the reprogramming process? Does the lymphocyte that is converted into an immature iPSC state “remember” that it used to be a lymphocyte? If yes, does this memory affect what types of cells the newly generated iPSCs can be converted into, i.e. are iPSCs derived from lymphocytes very different from iPSCs that are derived from skin cells?

There have been a number of recent studies that have tried to address the question of the “memory” in iPSCs, but two recent papers published in the January 3, 2013 issue of the journal Cell Stem Cell provide some of the most compelling proofs of an iPSC “memory” and also show that this “memory” could be used for therapeutic purposes. In the paper “Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells“, Vizcardo and colleagues studied the reprogramming of T-lymphocytes derived from the tumor of a melanoma patient. Mature T-lymphocytes are immune cells that can recognize specific targets, depending on what antigen they have been exposed to. The tumor infiltrating cells used by Vizcardo and colleagues have been previously shown to recognize the melanoma tumor antigen MART-1. The researchers were able to successfully generate iPSCs from the T-lymphocytes, and they then converted the iPSCs back to T-lymphocytes. What they found was that the newly generated T-lymphocytes expressed a receptor that was specific for the MART tumor antigen. Even though the newly generated T-lymphocytes had not been exposed to the tumor, they had retained their capacity to respond to the melanoma antigen. The most likely explanation for this is that the generated iPSCs “remembered” their previous exposure to the tumor in their past lives as T-lymphocytes before they had been converted to embryonic-like iPSCs and then “reborn” as new T-lymphocytes. The iPSC reprogramming apparently did not wipe out their “memory”.

This finding has important therapeutic implications. One key problem that the immune system faces when fighting a malignant tumor is that the demand for immune cells outpaces their availability. The new study suggests that one can take activated immune cells from a cancer patient, convert them to the iPSC state, differentiate them back into rejuvenated immune cells, expand them and inject them back into the patient. The expanded and rejuvenated immune cells would retain their prior anti-tumor memory, be primed to fight the tumor and thus significantly augment the ability of the immune system to slow down the tumor growth.

The paper by Vizcardo and colleagues did not actually show the rejuvenation and anti-tumor efficacy of the iPSC-derived T-lymphocytes and this needs to be addressed in future studies. However, the paper “Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation” by Nishimura and colleagues in the same issue of Cell Stem Cell, did address the rejuvenation question, albeit in a slightly different context. This group of researchers obtained T-lymphocytes from a patient with HIV, then generated iPSC and re-differentiated the iPSCs back into T-lymphocytes. Similar to what Vizcardo and colleagues had observed, Nishimura and colleagues found that their iPSC derived T-lymphocytes retained an immunological memory against HIV antigens. Importantly, the newly derived T-lymphocytes were highly proliferative and had longer telomeres. The telomeres are chunks of DNA that become shorter as cells age, so the lengthening of telomeres and the high growth rate of the iPSC derived T-lymphocytes were both indicators that the iPSC reprogramming process had made the cells younger while also retaining their “memory” or ability to respond to HIV.

Further studies are now needed to test whether adding the rejuvenated cells back into the body does actually help prevent tumor growth and can treat HIV infections. There is also a need to ensure that the cells are safe and the rejuvenation process itself did not cause any harmful genetic changes. Long telomeres have been associated with the formation of tumors and one has to make sure that the iPSC-derived lymphocytes do not become malignant. These two studies represent an exciting new development in iPSC research. They not only clearly document that iPSCs retain a memory of the original adult cell type they are derived from but they also show that this memory can be put to good use. This is especially true for immune cells, because retaining an immunological memory allows rejuvenated iPSC-derived immune cells to resume the fight against a tumor or a virus.

 

Image credit: “Surface of HIV infected macrophage” by Sriram Subramaniam at the National Cancer Institute (NCI) via National Institutes of Health Image Bank