Abstract
摘要:我們長期的研究目標是以毛囊再生治療各種疾病狀態下造成的禿髮,並釐清毛囊再生的機轉。禿髮是常見的問題,經常造成病人在社交上心裡的壓力。嚴重的禿髮無法以植髮治療,以生物工程的方法進行毛囊再生是近年來國際上毛囊研究的興趣。毛囊的構造及發育相當複雜,需要密切又精準的上皮-間質交互作用(epithelial-mesenchymalinteraction)。來自表皮及真皮的不同訊號,在適當的時間出現,進而造成毛囊發育。一般而言在成人,皮膚無法再自動進行毛囊胚胎發育的過程。不過,過去的研究顯示毛囊特化的間質細胞,稱為真皮乳頭細胞,可以誘導成人皮膚角質細胞轉分化為新的毛囊的構造。但此轉分化為毛囊的效率變異大。目前仍不清楚此轉分化過程中,何種細胞,例如角質幹細胞,短暫增生細胞或已分化細胞,實際上對此間質誘導訊息做出反應而新生成毛囊。此外,目前對此角質細胞轉轉分化為毛囊的分子機轉也不清楚。為了增進毛囊再生的效率,我們先前對真皮乳頭細胞進行研究,並提出一種促進毛囊真皮乳頭細胞自我聚集為可注入性並俱誘導能力微組織的方法。我們並證明此種微組織可以誘導初生鼠角質細胞生成毛囊(Young et al. Biomaterials 29:3521, 2008)。一般而言,成鼠的角質細胞對於真皮乳頭的毛囊誘導訊號反應較新生鼠皮差,因此較不易新生成毛囊。因此,除了真皮乳頭的誘導性訊號外,釐清成年皮膚角質細胞轉分化為毛囊構造的機轉,並促進其對真皮乳頭的毛囊誘導訊號的反應,將可提高成年後毛囊再生的效率。在此研究計畫中,我們試圖釐清關於角質細胞轉分化為毛囊構造的幾個根本問題,包括 (1)角質幹細胞在此轉分化為毛囊的過程,是否必要? (2) 真皮乳頭細胞是否可以誘導角質幹細胞以外的角質細胞轉分化為毛囊?(3)來自表皮及毛囊的角質細胞或角質幹細胞,是否會影響角質細胞轉分化為毛囊構造的效率?(4) 角質細胞轉分化為毛囊構造的分子機轉為何? (5) 受否可以透過對角質細胞的制約或誘導,可以增進角質細胞轉分化為毛囊構造的效率?基於上述長期的目標及我們試圖清的問題,在此三年計畫中我們有幾個研究目標,包括 (1) 釐清不同來源的角質細胞,是否影響角質細胞轉分化為毛囊構造 (2) 釐清角質細胞分化狀態對於角質細胞轉分化為毛囊的影響 (3) 釐清角質細胞對真皮乳頭誘導訊號反應而轉分化為毛囊時,角質細胞本身所需的分子訊息及訊息途徑。我們的研究不僅有助瞭解毛囊新生的機轉,也可以此作為其他發育及再生時牽涉上皮-間質交互作用之器官的重建。
Abstract: The long-term goal of our research is to regenerate hair follicles (HF) in adult life fortreatment of alopecia in various diseased statuses and to clarify the molecular mechanismgoverning the process of HF neogenesis. Alopecia or loss of HF is a common disorder andoften causes great psycho-social distress to the affected individuals. For severe alopecia inwhich HF transplantation can not be performed, bioengineering for HF regeneration is apromising alternative. HF development involves a delicate complex epidermal-mesenchymalinteraction (EMI), and , generally, neogenesis of HF by recapitulating HF morphogenesis inadult life does not happen in human. Alternatively, it has been shown that mesenchymal cellsof HF, so called dermal papilla (DP) cells, are able to transdifferentiate adult keratinocytes toform new HFs when they are transplanted in close proximity to adult keratinocytes. However,the efficiency for this transdifferentiation is variable and the identity of the keratinocytes, ie.keratinocyte stem cells, transient amplifying keratinocytes or differentiated keratinocytes, thatare able to respond to DP inductive cues is unknown. In addition, the molecular mechanismgoverning this transdifferentiation process is poorly understood.Aimed at increasing the efficiency of HF regeneration by engineering DP cells, we havedeveloped a method that facilitate self-assembling of DP cells into inductive injectablespheroidal microtissue and showed that these inductive DP microtissues are able to inducenew HFs from neonatal epidermal keratinocytes (Young et al. Biomaterials 29:3521, 2008).Generally, compared with fetal or neonatal keratinocytes, adult keratinocytes does not respondto DP inductive cues that well. In addition to strengthen inductive cues form DP cells,clarifying the mechanism of transdifferentiation of adult keratinocytes into HFs andenhancing the responsiveness of adult keratinocytes to mesenchymal inductive signals willfacilitate higher HF neogenesis efficiency.In this proposal, several fundamental questions regarding the transdifferentiation ofkeratinocytes into HF are asked: (1) Are keratinocyte stem cells needed in thetransdifferentiation process? (2) Can DP cells transdifferentiate keratinocytes with variousdifferentiated statuses into HF? (3) Can the origin of keratinocytes (or keratinocyte stem cells)affect the transdifferentiation process? (4) What is the molecular mechanism governing thetransdifferentiation of keratinocytes into HF structures? (5) Can we increase thetransdifferentiation efficiency by providing inductive cues for keratinocytes orpreconditioning keratinocytes?Based on the long-term objective and the questions stated above, there are several aimsto be achieved in this proposal: (1) To clarify effect of keratinocyte origin on thetransdifferentiation into HF. (2) To clarify the effect of differentiation status of keratinocyteson the transdifferentiation into HF under mesenchymal cues. (3) To clarify the molecularpathways required in keratinocytes for their transdifferentiation into HF and to increase theefficiency of transdifferentiation into HF by preconditioning keratinocytes. Our proposal willnot only shed light on the mechanism underlying transdifferentiation of keratinocytes into HFbut also pave way for regeneration of other organs that are dependent on EMI.
Keyword(s)
毛囊
再生
轉分化
角質細胞
幹細胞
真皮乳頭細胞
上皮-間質交互作
用
hair follicle
regeneration
transdifferentiation
keratinocyte
stem cell
dermal
papilla cell
epidermal-mesenchymal interaction