A Stem Cell Treatment for Hair Loss

Male and female pattern baldness involves the receding of the hair-line, hair loss and the thinning the hair covering on the scalp. Hair loss is also called alopecia and is a common problem among the elderly, those afflicted with certain diseases of the scalp, or those who take certain medicines. Hair life is not the end of life, but it can change someone’s appearance, affect their self-image, and affect someone’s emotional state. People with hair loss can use topical monoxidil (Rogaine), take an oral drug called finasteride (Propecia), or undergo a hair transplant. The drugs, however, must be used constantly or they stop working and hair transplants are horribly expensive.

Can stem cell-based treatment restore hair after it has been lost? Fortunately, a stem cell population called dermal papilla cells (DPCs), which are a type of mesenchymal stem cell population in hair follicles, have been identified and even characterized to some extent. DPCs are responsible for the formation of hair-follicles and play a very role in the process of hair cycling in which the hair shaft grows, is shed, is reestablished, and grows again. DPC might be useful for treating alopecia, but they do not survive when cultured outside the body, and this limitation has limited developing stem cell-based treatments for hair loss.

Now collaboration between two scientific research teams from Canada and China have resulted in a new way to use stem cells to treat hair loss.

A research team from the Nanfang Hospital of Southern Medical University, China, led by Zhi-Qi Hu and a Canadian team from the University of Manitoba, Canada, led by Malcolm Xing have designed a three-layered tunic that feeds and protects the DPCs and allows them to grow outside the body.

Xing describes this nutritive tunic as a “nutritious nano-clothing,” made of gelatin and alginate. These molecules can self-assemble and Hu and Xing and their coworkers encapsulated the cells within an inner layer of gelatin, a middle layer of alginate loaded with fibroblast growth factor-2, and an outer layer of gelatin. They call this method of encapsulation “layer-by-layer (LBL) nano-coating.”  This gelatin/alginate coating creates a protective microenvironment for cultured DPC and provides them with a significant source of a growth factor called fibroblast growth factor-2 (FGF2), which enhances proliferation of the DPCs and induces hair cell fates. The use of these three-layered tunics keeps the inductive signals close to the DPCs and circumvents the difficulties encountered in regenerating new hair follicles on bald skin.

DPC - hair follicle regeneration

When the Xing and Hu teams implanted these encased DPCs into the skin of nude mice, the implanted encapsulated cells generated the growth of abundant hair. The hair produced by these cells also was rooted in hair follicles that were normal in their appearance and function. The coating improvised by these teams greatly augmented the therapeutic capabilities of the DPCs by recapitulating the niche in which these cells are normally found. This stem cell niche induces the cells to secrete the native extracellular matrix that typically surrounds the cells and release the growth factors that keep the cells growing and in the proper stage of the cell cycle.

According to Xing, the most difficult part of this research project was “optimizing the concentrations of the coated polymers and manufacturing conditions to make the cells happy and healthy.”

Regenerative medicine researcher Oommen Varghese, from Uppsala University in Sweden, who was not involved in this work, said, “This is fascinating science that has enormous potential for clinical translational of stem cell based regenerative medicine. Such a coating could also protect cells from innate immunity, thereby improving the in vivo survivability. This is a major challenge in stem cell based translational research.”

Xing and his collaborators and colleagues would like to transform this technique from a laboratory bench to a clinical application that can be tested in human clinical trials.

ASTIC Clinical Trial Fails to Show Clear Advantage to Hematopoietic Stem Cell Transplantation as a Treatment for Crohn’s Disease

Patients with Crohn’s disease (CD) sometimes suffer from daily bouts of stomach pain and diarrhea. These constant gastrointestinal episodes can prevent them from absorbing enough nutrition to meet their needs, and, consequently, they can suffer from weakness, fatigue, and a general failure to flourish.

To treat Crohn’s disease, physicians use several different types of drugs. First there are the anti-inflammatory drugs, which include oral 5-aminosalicylates such as sulfasalazine (Azulfidine), which contains sulfur, and mesalamine (Asacol, Delzicol, Pentasa, Lialda, Apriso). These drugs, have several side effects, but on the whole are rather well tolerated. If these don’t work, then corticosteroids such as prednisone are used. These have a large number of side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity. More-serious side effects include high blood pressure, diabetes, osteoporosis, bone fractures, cataracts, glaucoma and increased chance of infection.

If these don’t work, then the stronger immune system suppressors are brought out. These drugs have some very serious side effects. Azathioprine (Imuran) and mercaptopurine (Purinethol) are two of the most widely used of this group. If used long-term, these drugs can make the patient more susceptible to certain infections and cancers including lymphoma and skin cancer. They may also cause nausea and vomiting. Infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia) are the next line of immune system suppressors. These drugs are TNF inhibitors that neutralize an immune system protein known as tumor necrosis factor (TNF). These drugs are also associated with certain cancers, including lymphoma and skin cancers. The next line of drugs include Methotrexate (Rheumatrex), which is usually used to treat cancer, psoriasis and rheumatoid arthritis, but methotrexate also quells the symptoms of Crohn’s disease in patients who don’t respond well to other medications. Short-term side effects include nausea, fatigue and diarrhea, and rarely, it can cause potentially life-threatening pneumonia. Long-term use can lead to bone marrow suppression, scarring of the liver and sometimes to cancer. You will need to be followed closely for side effects.

Then there are specialty medicines for patients who do not respond to other medicines or who suffer from openings in their lower large intestines to the outside world (fistulae). These include cyclosporine (Gengraf, Neoral, Sandimmune) and tacrolimus (Astagraf XL, Hecoria). These have the potential for serious side effects, such as kidney and liver damage, seizures, and fatal infections. These medications are definitely cannot be used for long period of time as their side effects are too dangerous.

If the patient still does not experience any relief, then two humanized mouse monoclonal antibodies natalizumab (Tysabri) and vedolizumab (Entyvio). Both of these drugs bind to and inhibit particular cell adhesion molecules called integrins, and in doing so prevent particular immune cells from binding to the cells in the intestinal lining. Natalizumab is associated with a rare but serious risk of a brain disease that usually leads to death or severe disability called progressive multifocal leukoencephalopathy. In fact, so serious are the side effects of this medicine that patients who take this drug must be enrolled in a special restricted distribution program. The other drug, vedolizumab, works in the same way as natalizumab but does not seem to cause this brain disease. Finally, a drug called Ustekinumab (Stelara) is usually used to treat psoriasis. Studies have shown it’s useful in treating Crohn’s disease and might useful when other medical treatments fail. Ustekinumab can increase the risk of contracting tuberculosis and an increased risk of certain types of cancer. Also there is a risk of posterior reversible encephalopathy syndrome. More common side effects include upper respiratory infection, headache, and tiredness.

If this litany of side effects sounds undesirable, then maybe a cell-based treatment can help Crohn’s patients. To that end, a clinical trial called the Autologous Stem Cell Transplantation International Crohn’s Disease or ASTIC trial was conducted and its results were published in the December 15th, 2015 edition of the Journal of the American Medical Association.

The ASTIC trial enrolled 45 Crohn’s disease patients, all of whom underwent stem cell mobilization with cyclophosphamide and filgrastim, and were then randomly assigned to immediate stem cell transplantation (at 1 month) or delayed transplantation (at 13 months; control group).  Blood samples were drawn and mobilized stem cells were isolated from the blood.  In twenty-three of these patients, their bone marrow was partially wiped out and reconstituted by means of transplantations with their own bone marrow stem cells. The other 22 patients were given standard Crohn disease treatment (corticosteroids and so on) as needed.

The bad news is that hematopoietic stem cell transplantations (HSCT) were not significantly better than conventional therapy at inducing sustained disease remission, if we define remission as the patient not needing any medical therapies (i.e. drugs) for at least 3 months and no clear evidence of active disease on endoscopy and GI imaging at one year after the start of the trial. All patients in this study had moderately to severely active Crohn’s disease that was resistant to treatment, had failed at least 3 immunosuppressive drugs, and whose disease that was not amenable to surgery.  All participants in this study had impaired function and quality of life.  Also, the stem cell transplantation procedure, because it involved partially wiping out the bone marrow, cause considerable toxicities.

Two patients who underwent HSCT (8.7%) experienced sustained disease remission compared to one control patient (4.5%). Fourteen patients undergoing HSCT (61%) compared to five control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months. Eight patients (34.8%) who had HSCTs compared to two (9.1%) patients treated with standard care regimens were free of the signs of active disease on endoscopy and radiology at final assessment.

However, there were 76 serious adverse events in patients undergoing HSCT compared to 38 in controls, and one patient undergoing HSCT died.

So increased toxicities and not really a clear benefit to it; those are the downsides of the ASCTIC study.  An earlier report of the ASTIC trial in 2013, while data was still being collected and analyzed was much more sanguine.  Christopher Hawkey, MD, from the University of Nottingham in the United Kingdom said this: “Some of the case reports are so dramatic that it’s reasonable to talk about this being a cure in those patients.”  These words came from a presentation given by Dr. Hawkey at Digestive Disease Week 2013.  Further analysis, however, apparently, failed to show a clear benefit to HSCT for the patients in this study.  It is entirely possible that some patients in this study did experience significant healing, but statistically, there was no clear difference between HSCT and conventional treatment for the patients in this study.

The silver lining in this study, however, is that compared to the control group, significantly more HSCT patients were able to stop taking all their immunosuppressive therapies for the three months prior to the primary endpoint. That is a potential upside to this study, but it is unlikely for most patients that this upside is worth the heightened risk of severe side effects. An additional potential upside to this trial is that patients who underwent HSCT showed greater absolute reduction of clinical and endoscopic disease activity. Again, it is doubtful if these potential benefits are worth the higher risks for most patients although it might be worth it for some patients.

Therefore, when HSCT was compared with conventional therapy, there was no statistically significant improvement in sustained disease remission at 1 year. Furthermore, HSCT was associated with significant toxicity. Overall, despite some potential upside to HSCT observed in this study, the authors, I think rightly, conclude that their data do not support the widespread use of HSCT for patients with refractory Crohn’s disease.

Could HSCT help some Crohn’s patients more than others? That is a very good question that will need far more work with defined patient populations to answer.  Perhaps further work will ferret out the benefits HSCT has for some Crohn’s disease patients relative to others.

The ASTIC trial was a collaborative project between the European Society for Blood and Marrow Transplantation (EBMT) and the European Crohn’s and Colitis Organization (ECCO) and was funded by the Broad Medical Foundation and the Nottingham Digestive Diseases Centers.