Start main content

Knowledge Exchange

banner
Back

Apr 26, 2021

Press Release: HKUMed identifies Collagen IV differentially regulates planarian stem cell potency and lineage progression: Striving towards tissue regeneration in humans

Press Release (2021-04-26):
Source: https://www.med.hku.hk/en/news/press/20210426-collagen-iv-planarian-stem-cell

HKUMed identifies Collagen IV differentially regulates planarian stem cell potency and lineage progression: Striving towards tissue regeneration in humans

Planarian

(A) Intact planarian / (B) Planarian immediately after amputation / (C,D) Regenerated fragments after 5 days of regeneration. Planarians can regenerate all missing tissue within one week of amputation, including a brain, eye spots and pharynx (feeding tube).

A research team of LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has identified a role of an extracellular matrix protein (ECM), Collagen IV, in the regulation of pluripotent stem cells in the regenerative flatworm (planarian). This collagen plays an important role in regulating how stem cells divide or change in the planarian, crucial to its regenerative capacity and can improve our understanding of human tissue regeneration. This study has been published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) [link to publication]. 

 

Planarian and the stem cell niche
The planarian uses its extensive supply of stem cells of high potency, conserved around 30% in adult worm, to regenerate any missing tissue, including even an entire brain after decapitation. How planarians can keep so many stem cells remains a mystery, and has fascinated biologists for over a century.

All stem cells have a home called a ‘niche’ and it is formed by different types of ECM proteins, including collagens. This provides important information to instruct stem cells how to behave, depending on the type of signals present. ECM is fundamental in the building of the surrounding environment of stem cells. Of these, Collagen IV is a very ancient ECM component in the basement membranes between epithelial tissues that has been highly conserved through evolution and is present in all mammals.

This study by researchers of the School of Biomedical Sciences, HKUMed has uncovered a means by which Collagen IV, a key building block of the niche of planarian stem cells, is involved in controlling how these stem cells are used in regenerating missing tissues. The extracellular matrix, in which Collagen IV is one of the components, is fundamental in the building of the surrounding environment of stem cells. This study also presents a major step forward in defining the home of high potency stem cells.

 

About the study
This study shows that the removal of Collagen IV in planarians will cause the stem cells to divide much faster, but lose their ability to become cells of other tissue types. This will lead to tissue breakdown but not regeneration. This study further linked Collagen IV to a molecular pathway involving a growth factor, nrg-7, produced by neurons. Nrg-7 stimulates stem cell proliferation, and is increased after removal of Collagen IV. However, this causes the stem cells to continue proliferating, and they are unable to turn into other cell types to repair or maintain planarian tissues. 

While daily wear and tear or mild damage to tissues and organs can be repaired by resident adult stem cells, repair of or regeneration from major injuries is not possible in human beings. This will require stem cells with higher potency in the right environment to kick-start the process. Since our current understanding of how to regenerate tissues and organs in humans is still limited, deciphering how planarians utilise Collagen IV to keep high potency stem cells in an adult worm, which mammals cannot do, paves the way towards unlocking the mystery and wonders of tissue regeneration in humans.

Professor Danny Chan, Assistant Dean (Research Postgraduate Studies), HKUMed and Professor at the School of Biomedical Sciences, S Y and H Y Cheng Professorship in Stem Cell Biology and Regenerative Medicine, who initiated the study, said, ‘The immortality of an animal under the knife fascinates me as a scientist. What’s more, each cut part can become a new animal blows my mind. The planarian in this study can do just that, a feat enabled by the ability to keep many stem cells as an adult, and to use them in the regenerative process. The planarian can become a new planarian after being cut into several parts, its ability to keep many stem cells and use them in the regenerative process inspired our research. Our finding of an extracellular matrix protein as part of the environment in which planarians can keep stem cells is an important step, with the hope that we can mimic this in humans to rebuild missing tissues. As a bone biologist, I would like to see one day, we can regrow a missing digit.’

The possibility of regenerating missing tissues in human beings is a fascinating dream, and understanding how other organisms such as planarians can achieve such tissue regeneration brings us one step closer in realising this feat in mammalian systems. Future studies that add to our understanding of the ECM in regenerative animals such as the planarian would enable us to use this information in building a suitable ‘niche’ for human stem cells. One such goal would be able to build an artificial stem cell ‘niche’ capable of housing a large number of human stem cells, which can then be applied to damage sites and used to help regenerate tissues.

 

About the research team
The study was conducted by Professor Danny Chan’s research group, including Dr Andy Chan Shing-fung, former Research Associate, and Dr Sophia Ma Ka-yan, Post-doctoral Fellow at School of Biomedical Sciences, HKUMed. The second corresponding author is Dr Bret J. Pearson from Department of Molecular Genetics, University of Toronto; Program in Developmental and Stem Cell Biology, The Hospital for Sick Children; and Ontario Institute for Cancer Research, Toronto, Canada (three affiliations). 

 

Acknowledgements
This work was supported by the S Y and H Y Cheng Professor endowment in Stem Cell Biology and Regenerative Medicine (to Professor Danny Chan). Dr Bret J. Pearson was supported by Ontario Institute for Cancer Research Grant IA-026.

 

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).

港大醫學院發現第四型膠原蛋白能調控渦蟲多功能幹細胞 揭示人類組織再生潛能

Planarian

(A) 完整的渦蟲/(B) 渦蟲被切斷後的即時形態/(C,D) 組織再生五天後的形態;渦蟲能在一周內再生所有缺失組織,包括腦、眼斑及咽喉(餵食管)。

香港大學李嘉誠醫學院(港大醫學院)一項最新研究確定了第四型膠原蛋白──一種細胞外基質蛋白(ECM)──在具有再生能力的扁蟲(渦蟲)裡有調控多功能幹細胞的作用。第四型膠原蛋白在渦蟲中是調控幹細胞如何分裂或演變的重要一環,也是渦蟲能再生組織的關鍵。是次研究成果有助加深我們對人類組織再生潛能的理解。相關研究成果已在《美國國家科學院院刊》發表(按此瀏覽期刊文章)。

 

渦蟲和幹細胞的「家」
渦蟲的成蟲在成長過程中能保存大量(約三成)的高效幹細胞,如有任何組織缺失,甚至斷頭後,也能再生組織,讓大腦重生。渦蟲為何能保存大量高效幹細胞,至今仍是未解的謎團;但過去一個多世紀以來,生物學家為此著迷不已。

所有幹細胞都有一個由不同類型的細胞外基質蛋白(包括膠原蛋白)組成、被稱為「生態位」的「家」。這個「家」會發出不同的信號,指示幹細胞運作。細胞外基質蛋白是構建幹細胞周遭環境的基礎──其中第四型膠原蛋白是非常原始的細胞外基質成分,存在於上皮組織之間的基底膜,哺乳類動物在演化過程中亦保存了相似的結構或序列。

港大醫學院生物醫學學院的研究團隊在是次研究發現,第四型膠原蛋白作為渦蟲幹細胞生態位的關鍵組成部分,如何參與調控利用幹細胞的方式,使缺失組織重生的機制。因為細胞外基質是構建幹細胞周遭環境的基礎,第四型膠原蛋白就是基質其中一種成分。是項研究為定義高效幹細胞的「家」邁出了重要的一步。

 

研究詳情
是項研究發現,移除渦蟲體內的第四型膠原蛋白將能導致幹細胞加速分裂,但分裂出來的細胞卻失去成為其他組織類型細胞的能力,以致組織破裂而非再生。研究團隊進一步帶出第四型膠原蛋白與一個分子途徑的關聯,該分子途徑涉及由神經元產生的生長因子Nrg-7,而Nrg-7會刺激幹細胞增殖,在移除第四型膠原蛋白後效果更會加強。然而,這些增殖出來的幹細胞始終無法變成其他類型的細胞,以修護或保留渦蟲的組織。

儘管人類的組織和器官在日常損耗或輕度損傷後,可以通過成體的幹細胞來修復,但是人類在嚴重損傷的情況下,卻無法自我修復或再生。要展開這自我修復或再生過程,將需要在合適的環境下使用更高效的幹細胞。然而,目前我們對於人類組織和器官再生的認知仍然有限,透過了解渦蟲如何利用第四型膠原蛋白,例如渦蟲的成蟲能保留三成幹細胞這種哺乳類動物無法達成的事,將有助我們解構在人類實踐組織再生的奧秘。

領導是項研究的港大醫學院助理院長(研究生課程)、生物醫學學院教授、鄭兆如鄭杏如基金教授(幹細胞生物學及再生醫學)陳振勝教授表示:「能在刀下不朽的生物深深吸引作為科學家的我,令我更震驚的是渦蟲被切成幾份後仍能生存,甚至保存很多幹細胞,並再生成另一條渦蟲的能力,啟發了我們的研究──渦蟲成蟲在含細胞外基質蛋白的環境下仍能保存很多幹細胞,這一步非常重要,為人類重建缺失組織帶來希望。身為骨骼生物學家,我期望有一天可以看到人類重新長出失去了的身體部分。」

發掘人類再生缺失組織的潛力,是一個引人入勝的夢想,透過了解如渦蟲等生物怎樣重生其缺失的組織,將有助推動在哺乳類動物身上進行相關研究。日後有關再生動物如渦蟲身上的細胞外基質蛋白的研究,將加深我們對這方面的認識,並以此為基礎,嘗試為人類幹細胞建造生態位。其中一項長遠目標是於建造能儲存大量人類幹細胞的人造生態位,以應用於受損部位,協助缺失組織再生。

 

研究團隊
本研究是由港大醫學院助理院長(研究生課程)、生物醫學學院教授、鄭兆如鄭杏如基金教授(幹細胞生物學及再生醫學)陳振勝教授的研究團隊完成,其他研究人員包括前副研究員陳承峰博士及博士後研究員馬家欣博士。第二通訊作者為多倫多大學分子遺傳學系、多倫多病童醫院發育及幹細胞生物課程及加拿大安大略癌症研究所的Bret J. Pearson博士。

 

鳴謝
是項研究得到鄭兆如鄭杏如基金(幹細胞生物學及再生醫學)及加拿大安大略癌症研究所撥款IA-026的資助。

 

傳媒查詢
請聯絡香港大學李嘉誠醫學院(電郵︰medmedia@hku.hk)。