Stress-Resistant Stem Cells From Fat


During liposuction patients lose a fat cells, fat-based mesenchymal stem cells, and now, according to new results from UCLA scientists, stress-enduring stem cells.

This new stem cell population has been called a Multi-lineage Stress-Enduring Adipose Tissue or Muse-AT stem cells. UCLA scientists found Muse-AT stem cells by accident when a particular machine in the laboratory malfunctioned, killing all the cells found in cells from human liposuction, with the exception on the Muse-AT stem cells.

Gregorio Chazenbalk from the UCLA Department of Obstetrics and Gynecology and his research team discovered, after further tests on Muse-AT stem cells, that they not only survive stress, but might be activated by it.

The removal of Muse-AT stem cells from the human body by means of liposuction revealed cells that express several embryonic stem cell-specific proteins (SSEA3, TR-1-60, Oct3/4, Nanog and Sox2). Furthermore, Muse-AT stem cells were able to differentiate into muscle, bone, fat, heart muscle, liver, and neuronal cells. Finally, when Chazenbalk and his group examined the properties of Muse-AT stem cells, they discovered that these stem cells could repair and regenerate tissues when transplanted back into the body after having been exposed to cellular stress.

Muse-ATs express pluripotent stem cell markers. Immunofluorescence microscopy demonstrates that Muse-AT aggregates, along with individual Muse-AT cells, express characteristic pluripotent stem cell markers, including SSEA3, Oct3/4, Nanog, Sox2, and TRA1-60. Comparatively, ASCs (right panel) derived from the same lipoaspirate under standard conditions (see above, [16] were negative for these pluripotent stem cell markers. Nuclei were stained with DAPI (blue). Original magnification, 600 X. doi:10.1371/journal.pone.0064752.g002
Muse-ATs express pluripotent stem cell markers.
Immunofluorescence microscopy demonstrates that Muse-AT aggregates, along with individual Muse-AT cells, express characteristic pluripotent stem cell markers, including SSEA3, Oct3/4, Nanog, Sox2, and TRA1-60. Comparatively, ASCs (right panel) derived from the same lipoaspirate under standard conditions (see above, [16] were negative for these pluripotent stem cell markers. Nuclei were stained with DAPI (blue). Original magnification, 600 X.
doi:10.1371/journal.pone.0064752.g002
“This population of cells lies dormant in the fat tissue until it is subjected to very harsh conditions. These cells can survive in conditions in which usually cancer cells can survive. Upon further investigation and clinical trials, these cells could prove a revolutionary treatment option for numerous diseases, including heart disease, stroke and for tissue damage and neural regeneration,” said Chazenbalk.

Purifying and isolating Muse-AT stem cells does not require the use of a cell sorter or other specialized, high-tech machinery. Muse-AT stem cell can grow in liquid suspension, where they grow as small spheres or as adherent cells that pile on top of each other to form aggregates, which is rather similar to embryonic stem cells and the embryoid bodies that they form.

Isolation and morphologic characterization of Muse-ATs. (A) Schematic of Muse-AT isolation and activation from their quiescent state by exposure to cellular stress. Muse-AT cells were obtained after 16 hours, with incubation with collagenase in DMEM medium without FCS at 4°C under very low O2 (See Methods). (B) FACS analysis demonstrates that 90% of isolated cells are both SSEA3 and CD105 positive. (C) Muse-AT cells can grow in suspension, forming spheres or cell clusters as well as individual cells (see red arrows) or (D) Muse-AT cells can adhere to the dish and form cell aggregates. Under both conditions, individual Muse-AT cells reached a diameter of approximately 10µm and cell clusters reached a diameter of up to 50µm, correlating to stem cell proliferative size capacity. doi:10.1371/journal.pone.0064752.g001
Isolation and morphologic characterization of Muse-ATs.
(A) Schematic of Muse-AT isolation and activation from their quiescent state by exposure to cellular stress. Muse-AT cells were obtained after 16 hours, with incubation with collagenase in DMEM medium without FCS at 4°C under very low O2 (See Methods). (B) FACS analysis demonstrates that 90% of isolated cells are both SSEA3 and CD105 positive. (C) Muse-AT cells can grow in suspension, forming spheres or cell clusters as well as individual cells (see red arrows) or (D) Muse-AT cells can adhere to the dish and form cell aggregates. Under both conditions, individual Muse-AT cells reached a diameter of approximately 10µm and cell clusters reached a diameter of up to 50µm, correlating to stem cell proliferative size capacity.
doi:10.1371/journal.pone.0064752.g001

We have been able to isolate these cells using a simple and efficient method that takes about six hours from the time the fat tissue is harvested,” said Chazenbalk. “This research offers a new and exciting source of fat stem cells with pluripotent characteristics, as well as a new method for quickly isolating them. These cells also appear to be more primitive than the average fat stem cells, making them potentially superior sources for regenerative medicine.”

Embryonic stem cells and induced pluripotent stem cells are the two main sources of pluripotent stem cells. However, both of these stem cells have an uncontrolled capacity for differentiation and proliferation, which leads to the formation of undesirable teratomas, which are benign tumors that can become teratocarcinomas, which are malignant tumors. According to Chazenbalk, little progress has been made in resolving this defect (I think he overstates this).

Muse-AT stem cells were discovered by a research group at Tokohu University in Japan and were isolated from skin and bone marrow rather than fat (see Tsuchiyama K, et al., J Invest Dermatol. 2013 Apr 5. doi: 10.1038/jid.2013.172). The Japanese group showed that Muse-AT stem cells do not form tumors in laboratory animals. The UCLA group was also unable to get Muse-AT stem cells to form tumors in laboratory animals, but more work is necessary to firmly establish that these neither form tumors nor enhance the formation of other tumors already present in the body.

Chazenbalk also thought that Muse-AT stem cells could provide an excellent model system for studying the effects of cellular stress and how cancer cells survive and withstand high levels of cellular stress.

Chazenbalk is understandable excited about his work, but other stem cells scientists remain skeptical that this stem cells population has the plasticity reported or that these cells are as easily isolated as Chazenbalk says.  For a more skeptical take on this paper, see here.

Rats with Premature Birth-Type Brain Damage Show Neurologic Improvement After Stem Cell Transplants


Can stem cells transferred into the brains of newly-born babies with brain damage reverse brain damage? A study presented at the Society for Maternal-Fetal Medicine’s annual meeting in Dallas, Texas, researchers suggests that such a treatment might actually work. In this study, early transplantation of human placenta-derived mesenchymal stem cells into the lateral ventricles of neonatal rats with birth-related brain damage is feasible in this animal model. The transplanted donor cells survive and migrate within the recipient’s brain. Researchers designed this study so that the rat’s brain damage would mimic the type of brain injury observed in infants with very low birth weight.

Preterm delivery is one of the major causes of neonatal brain damage. Despite all efforts to prevent it, survivors of premature birth often suffer from some kind of injury to the brain. Survivors of preterm labor often display cognitive, behavioral, attention related and/or socialization deficits in twenty-five to fifty percent of cases; and major motor deficits in five to ten percent of cases.

Those infants with very low birth weights compose the majority of neonatal encephalopathy Such infants present with hypoxia-ischemia (low oxygen delivery to the tissues, which results in cell death and tissue damage) and inflammation. Approximately 63,000 infants are born in the United States with a very low birth weight (one to five percent of all live births). In order to understand the pathology of very premature infants, and if stem cells could ameliorate their conditions, this study, Early Intracranial Mesenchymal Stem Cell Therapy After a Perinatal Rat Brain Damage, was undertaken. This study investigated the neuroprotective effects of transplanted mesenchymal stem cells in recently born rats that had brain injuries that mimicked those found in infants with a very low birth weight.

One of the study’s authors, Martin Müller, MD, of the University of Bern, Obstetrics and Gynecology, Bern, Switzerland, said: “Stem cells are a promising source for transplant after a brain injury because they have the ability to divide throughout life and grow into any one of the body’s more than 200 cell types, which can contribute to the ability to renew and repair tissues. In our study, the donor cells survived, homed and migrated in the recipient brains and neurologic improvement was detected.”

Examination of the level of brain damaged after mesenchymal stem cell treatment indicated that stem cells exerted a neuroprotective effect on the brain. The transplanted cells survived in the brain, homed to damaged areas and migrated throughout the recipient brains. Furthermore, a combination of mesenchymal stem cells and erythropoietin (the signaling molecule made by the kidneys to signal to the bone marrow to make more red blood cells) might work even better.

While this work is still ongoing, it shows that such stem treatments are feasible and exert some positive effects.