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Adv. Mater. of the "Chunming Sugar Water" team of the University of Macau: Oligosaccharide biomaterials that promote hair follicle regeneration

Hair loss affects more than 50 million people worldwide. However, the existing clinical treatments are very limited, and the price and pain of hair transplantation also prohibit many people. Developing safe, effective and new methods with clear mechanisms to promote hair regeneration will have significant clinical significance and commercial value. Recently, Professor Wang Chunming of the University of Macau, together with the team of Professor Dong Lei of Nanjing University and researcher Xiao Jian of Wenzhou Medical University, reported that a glucomannan oligosaccharide (OG6) obtained through enzymatic hydrolysis can selectively stimulate the release of CCL5 chemokine. Modulating the local immune microenvironment to promote hair follicle growth was published as a research paper in the journal Advanced Materials.

In healthy skin tissue, the local accumulation of regulatory T cells (Treg) in hair follicles is very important for activating hair follicle stem cells and promoting hair follicles to enter the anagen phase from the resting phase. Inspired by the mechanism by which skin tissue recruits Tregs to balance excessive inflammation under pathological conditions of microbial invasion, the research team hopes to guide such cells to accumulate near hair follicles. However, existing methods are difficult to accurately induce the local release of specific chemokines in tissues and recruit specific cells; instead, they usually induce the phenotypic polarization of macrophages, release a variety of cytokines and chemokines, and induce inflammation or Other excessive immune responses affect treatment efficacy and safety. Moreover, the direct release of specific cytokines (usually in the form of recombinant proteins) often diffuses and degrades rapidly in the body, and excessive use can cause strong side effects.

The joint research team has been using glucomannan as a model material in recent years to explore new methods that can promote tissue repair by regulating the immune microenvironment. Researchers have observed that other polysaccharide molecules present in microorganisms or mammalian extracellular matrices often exhibit the phenomenon of "activity masking": that is, a certain polysaccharide as a whole shows an activity (or even no activity), but Different fragments may have significantly different (or even diametrically opposed) activities; they hypothesized that the specific activity of a specific fragment may be "masked" in a higher degree of polymerization by stripping and Screening for these fragments may unmask these functions. After trying a variety of glycosidases to analyze the degradation of glucomannan raw materials with a length of about 400 sugar units, they selected a cellulase (EC 232-734-4), which can obtain different results after different degradation times. Combined degradation products. Interestingly, gene chip data found that one of the components, named OG6, can stimulate mouse bone marrow-derived primary macrophages to selectively release the CCL5 chemokine, while keeping other factors at a low expression state. It does not induce the polarization of macrophages towards any inflammatory/anti-inflammatory phenotype. However, other components obtained from degradation that are larger (e.g., 15 sugar units; GM15) or smaller (e.g., OG1-OG5) are either unable to upregulate the expression of chemokines or can stimulate multiple The secretion of factors lacks the selective regulatory function of OG6 (Figure 1).

Figure 1. Researchers use cellulase (EC 232-734-4) to degrade high-polymerized glucomannan to obtain poly/oligosaccharide components of different sizes with lower polymerization degrees, among which OG6 can stimulate mouse bone marrow. Source macrophages secrete CCL5 but do not significantly affect the expression of other chemokines or genes related to cell polarization.

Based on the detailed characterization of the composition and structure of OG6, the researchers obtained Treg cells from the spleens of Foxp3 reporter mice and observed that macrophages stimulated by OG6 could induce Treg cell migration through paracrine. They further used molecular docking simulation, MST Molecular interaction experiments and a series of cell biology tests demonstrated the key role of macrophage mannose receptor (MR) and intracellular NOD1/2 pathway in mediating the activation of macrophages by OG6. Subsequently, the team established a mouse back hair removal model and injected OG6 subcutaneously. After 10 days, hair growth was much more significant than that in the control group. The structure of the new hair was good. Treg cells around the hair follicles gathered around CD34+ cells and stimulated their proliferation on the 5th day. The hair follicles entered the IIIa and IIIc growth phases on the 7th and 10th days (Figure 2). Interestingly, researchers found for the first time that subcutaneous injection of CCL5 recombinant protein as a control group can also stimulate hair growth, but the effect is weaker than OG6 and uneven. It also induces stronger inflammation, which may be related to the exogenous recombinant protein in the body. Easily degraded and inactivated. In contrast, in addition to showing better activity, OG6's degradation products are also substances that originally exist in the body such as glucose and mannose, so it may have higher safety, providing an important theory for subsequent research and clinical translation. in accordance with.

figure 2. The researchers observed that OG6 can promote hair growth in mice and characterized the biological process by which it stimulates hair follicles to enter the anagen phase.

This research uses an ingenious "unmasking" method to obtain more specific immune activity. It is expected to develop a set of technical methods to accurately obtain and control the activity of sugar molecules, enriching the development strategies of sugar biomaterials and related drugs or medical devices. (image 3). This research was supported by the Macao Science and Technology Development Fund "Macao Key Research and Development Plan 0001/2021/AKP", the National Natural Science Foundation of China Outstanding Youth Science Fund, and the Shenzhen Science and Technology Innovation Commission Category C Science and Technology Project Fund. The research team has obtained relevant patent authorization and started clinical translation work.

Figure 3. Modulating the local immune microenvironment to promote hair regeneration through the biological activity of enzymatically hydrolyzed "unmask" glucomannan.

Original paper:

https://doi.org/10.1002/adma.202304655