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Cytokine Archives | Hair Loss Cure 2020 Note: If you have any questions for Dr. Malcolm Xing, please add them in a comment to this post and I will collect the best ones and send them to him in a few days if there is sufficient interest.
About one week ago, a very interesting article was published in the Journal of Materials Chemistry B. They actually have “A”, “B”, and “C” versions, with the “B” version being connected to Biology. The title of this article was “Cytokine loaded layer-by-layer ultrathin matrices to deliver single dermal papilla cells for spot-by-spot hair follicle regeneration . ”
For the non-scientist type people that most of the world is composed of, an easier to understand and more succinct title was postulated in an article in Chemistry Journal: “Re-seeding hairlines with stem cells. ” I have always felt that the scalp is exactly like a garden and can be entirely reseeded in the future once scientists figure out the right method of doing so.
The approach to cure hair loss that was taken by this study’s authors is quite unique (see interview below for more on that). Moreover, this research entails a multinational collaboration between Canadian (led by Dr. Malcolm Xing ) and Chinese (led by Dr. Zhi-Qi Hu ) researchers. I was happy to finally get news on hair loss research in China, a country that I have neglected in my Worldwide Hair Loss Research page. Primarily due to language issues and my lack of effort and motivation in trying to comb through Chinese search engines such as Baidu.
I wanted to discuss this journal article last week, but was unsure about devoting a whole post to it. Then I decided to try my luck and see if either Dr. Xing or Dr. Hu were willing to conduct an interview with me via e-mail. Luckily Dr. Xing was willing, despite being on vacation this past week. I had to delay this post until he responded.
Please do not e-mail him yourself as he is probably swamped with inquiries related to this paper in addition to ongoing other research at his lab. You can post questions in the comments section of this post, and after a few days I will send them all to him in bulk. He has told me that he can reply to some more of my questions, but I am unwilling to bother him more than one more time.
Interview with Dr. Xing Question 1) How applicable is your mouse model to a human model? Can you try this experiment on human dermal papilla cells without needing any official government approval (either in Canada or China or in both)?
Answer 1) Mouse model only provides us some primary support for further study in human cells and finally in a human model. No, we need official government approval.
Question 2) I assume you only worked on mice-to-mice DPC transplantation based on the image I saw of your work in Chemistry World magazine , but I have not read your whole paper as it is not yet publicly available on Google Scholar. Or did you also move human dermal papilla cells to mice?
Answer 2) Not yet for human dermal papilla cells.
Question 3) There has been an ever increasing amount of research done on dermal papilla cells in the hair loss world over the past few years e.g.,
Have you seen any work that is similar to yours? Any that is different, but that still interests you? Have you ever tried to collaborate with the Rendl lab?
Answer 3) Yes, there are similar works to ours. Only difference in what we did is just to give the dermal papilla cell very thin clothing for cellular function tuning. We didn’t get a chance to contact Dr. Rendl, but we are open to all kinds of collaboration .
Question 4 and 5) Dr. Jeff Biernaskie from Canada (see https://www.hairlosscure2020.com/the-university-of-calgary-hair-loss-research/ ) and a company called Replicel (also from Canada — see http://replicel.com/product-pipeline/rch-01-hair-regeneration/ ) have both done work on dermal sheath cup cells. Can you describe the difference in working with dermal sheath cup cells versus dermal papilla cells?
Why are some researchers focusing on the former, and some on the latter?
Answer 4) and 5) They are cellular biological based and we are biomaterials oriented. We are biomaterial engineers and study the hair regeneration from biomaterials and nanotechnology perspective to create a bioengineering microenvironment for cell growth. [My note: Dr. Xing provided separate answers to my two related questions, but I it seems like he did not address the difference between choosing the dermal papilla versus dermal sheath cup cell areas of research. Perhaps there is not much difference there, and to be honest, I did not try to find out prior to asking that question ].
Question 6) Have you had a chance to look at Dr. Colin Jahoda’s work (he has covered dermal papilla cells as far back as the early1980s)? He has recently coauthored papers on 3D papilla spheroids (http://www.pnas.org/content/110/49/19679.full.pdf ) and it seems like this is one way of restoring dermal papilla inductivity. Your method of ‘nutritious nano-clothing ’ seems like a totally different approach and perhaps has an even higher chance of success. However, I am not a scientist and can not differentiate between the work of all the researchers that I have mentioned in this e-mail thus far. Has your method ever been tried by other scientists? Do you think it is easier than what Dr. Jahoda is attempting?
Answer 6) Actually, Dr. Jahoda’s work gave us the inspiration for this study. In our another new work (to be submitted), we already combined currently published nano-clothing with 3D spheroids for hair regeneration. It’s very difficult for me to say which one is easier. I enclosed several publications from our lab about nano-clothing and spheroids for tissue engineering.
Question 7 and 8) The ending of the article about your work in Chemistry World magazine has the following sentence: “Xing is currently trying to move the technology from the bench to the bedside.” What will it take to get this goal realized? Would you have to undergo clinical trials in a similar manner to the US (or in a similar manner to what Replicel is doing in Canada/Japan)?
If so, it would easily take five years, by which time I think a cure for hair loss will already be here. Replicel and its Japanese partner Shiseido themselves are approaching final clinical trials (in Japan, the government is speeding up the clinical trial process so many US companies are moving there to conduct final trials). Do you have confidence that your work can come to the bedside before the end of 2020? Would you need funding to get this work moving along?
Answer 7 and 8) Yes, we are trying to apply this trial in China. China has similar regulations to the US. Currently, several Chinese industry partners show their interests in collaborations. There potential partners have already biomedical products approved by China FDA. Right now, I am also looking forward to the industry collaboration from Canada.
Not sure for these final trials before the end of 2020, but we are working at this goal. Yes, we need funds from government and industry to move this application forward.
Question 9) How did you decide to include fibroblast growth factor-2 (FGF-2) in your experiment? There seem to be other fibroblast growth factors (e.g., FGF-1, FGF-7, FGF-10) that promote hair growth too, but I assume you preferred FGF-2)?
Answer 9) FGF-2 is the preferred growth factor from our clinic collaborator; however, we can put more than one GF in the nano-clothing.
Question 10) On my blog, I have a page listing key global centers of hair loss research (https://www.hairlosscure2020.com/hair-loss-research-around-the-world/ ). I have neglected research in China for the most part due to limited information availability. I only include centers/universities/labs that devote significant resources to hair loss research and are not just coming out with one hair loss research related study every few years. Do you think that Nanfang Hospital of Southern Medical University in China has any department devoted to hair loss research? If you know of any other Chinese universities or institutions that are undertaking regular research on hair loss, please let me know and I will add it to my page on global centers of hair loss research.
Answer 10) As to my knowledge, a team of more than 10 clinical doctors is working on hair loss in the Dept. Plastic Surgery, Nanfang Hospital. I just came back from that department for the collaboration when I got your email.
Question 11) On your tissue engineering website (http://www.tissueengineering.ca/ ) there is nothing about hair loss research, although the site has not been updated recently. How serious is your lab about hair loss research versus all the other types of tissue engineering research that you focus on?
Answer 11) We didn’t get the chance to update the web but we have more than 6 researchers work on this theme.
Thank you!
Update: Found an interesting article covering some of Dr. Xi’s work in the medical field.
Hair loss news blog. Hair cloning for baldness.