Fat-Based Stem Cell Treatment Suggests a New Way to Slow Scarring in Scleroderma Patients

Scleroderma is an autoimmune disease that causes chronic scarring of the skin and internal organs. The deposition of massive quantities of collagen decrease the pliability and elasticity of the skin, lungs, and blood vessels. As you might guess, the prognosis of scleroderma patients is quite poor and this disease causes a good deal of suffering and morbidity.

Treatments options usually include steroids, and other drugs that suppress the immune system, all of which have severe side effects.

New research from scientists at the Hospital for Special Surgery in New York City and other collaborating institutions, led by Dr. Teresa T. Lu, may have identified a new mechanism in operation during the onset and maintenance of scleroderma. This work was published in the Journal of Clinical Investigation.

In this study, scleroderma patients were shown to possess diminished numbers of “adipose-derived stromal cells” (ADSCs) in the layer of fat that underlies the upper layers of the skin. These fatty tissues are referred to as “dermal white adipose tissue.” The loss of these dermal white adipose tissue ADSCs tightly correlates with the onset of scarring in two different mouse model systems that recapitulate scleroderma in laboratory mice. These observations may show that ADSC loss contributes to scarring of the skin.

Why do these ADSCs die? Lu and her coworkers discovered that ADSC survival depends on the presence of particular molecules secreted by immune cells called “dendritic cells.” Skin-based dendritic cells secrete a molecule called lymphotoxin B. Although this molecule is called a toxin, it is required for ADSC survival. In laboratory mice that suffered from a scleroderma-like disease, artificial stimulation of the lymphotoxin B receptor in ADSCs amplified and eventually restored the numbers of ADSCs in the skin. Could stimulating ADSCs in this manner help treat scleroderma patients?

According the Dr. Lu, the administrating author of this publication, injecting “ADSCs is being tried in scleroderma; the possibility of stimulating the lymphotoxin B pathway to increase the survival of these stem cells is very exciting.” Dr. Lu continued, “By uncovering these mechanisms and targeting them with treatments, perhaps one day we can better treat the disease.”

Lu also thinks that a similar strategy that targets stem cells from other tissues might provide a treatment for other rheumatological conditions – such as systemic lupus erythematosis and rheumatoid arthritis. Additionally, bone and cartilage repair might also benefit from such a treatment strategy.

In the coming years, Dr. Lu and her colleagues hope to test the applicability of this work in human cells. If such a strategy works in human cells, then the next stop would be trial in human scleroderma patients. The success of such a treatment strategy would be a welcome addition to the treatment options for scleroderma patients, but only if this treatment is shown to be proven safe and effective.

“Improving ADSC therapy would be a major benefit to the field of rheumatology and to patients suffering from scleroderma,” said Lu.

Rare Stem Cell Heals Damaged Lungs; Notch Signaling May Hold the Key to Lung Fibrosis

Patients who survive an acute lung injury are able to recover their lung function, which suggests that adult lungs regenerate to a certain extent. Depending on the cause and severity of the injury, multiple progenitor cells, including alveolar type II cells and distal airway stem cells, have been shown to drive lung tissue regeneration in mice. Now, Andrew Vaughan and others have described another cell type in the lungs involved in the repair process in mice when mouse lungs are damaged from influenza virus infection or inhalation of the anticancer drug bleomycin.  This cell type is called the rare lineage-negative epithelial progenitor (LNEP).

LNEP cells are quiescently present within normal distal mouse lung and do not express mature lineage markers (for example, a protein called club cell 10 or CC10 or surfactant protein C, otherwise known as SPC).  However, Vaughan and others demonstrate that LNEPs are activated to proliferate and migrate to damaged sites and mediate lung remodeling following major injury.

Vaughan and others used lineage tracing approaches and cell transplantation strategies and showed that LNEP cells, but not mature epithelial lineage cells, are multipotent in their ability to give rise to both club cells and alveolar cells.  Interestingly, activation of the Notch signaling pathway in LNEP cells initially activated them, but persistent Notch activation inhibited subsequent alveolar differentiation, resulting in failed tissue regeneration (characterized by the formation of abnormal honeycomb cysts in the mouse lung).  Thus Notch signaling is only required at the beginning of their activation, and then must be down-regulated if the LNEP cells are to reconstruct normal lung tissue.  Interestingly, scarred over or fibrotic lungs from patients with idiopathic pulmonary fibrosis or a disease called scleroderma show evidence of hyperactive Notch signaling and their lungs also contain very similar-looking honeycomb cysts.  This strongly suggests that dynamic Notch signaling also regulates the function and differentiation of LNEP-analogous human lung progenitor cells.  Thus designing treatments that properly regulate Notch signaling and, consequently, LNEP activity may potentially halt the development of lung fibrosis in humans.