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研究生：	陳柏予 Chen, Po-Yu
論文名稱：	探討 DDR1 在腎臟纖維母細胞中的機械力生物學功能並探索非洲針刺鼠腎臟再生的潛在機制 To investigate the mechanobiological function of DDR1 in renal fibroblasts and explore the mechanisms underlying renal regeneration in Acomys
指導教授：	湯銘哲 Tang, Ming-Jer
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2026
畢業學年度：	114
語文別：	英文
論文頁數：	153
中文關鍵詞：	腎臟纖維化、細胞外基質恆定、膠原蛋白受體、足體、開羅刺鼠
外文關鍵詞：	renal fibrosis, ECM homeostasis, collagen receptor, podosome, Acomys cahirinus
相關次數：	點閱：17 下載：0
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腎臟纖維化是慢性腎臟病常見的病理特徵，主要由持續性的纖維母細胞活化、細胞外基質累積及組織硬化所驅動。本研究探討膠原蛋白受體 DDR1 在腎臟纖維母細胞中的機械力生物學角色，並進一步探索具再生能力的哺乳動物:非洲針刺鼠(Acomys cahirinus) 其抗纖維化腎臟修復背後的潛在機制。
透過小鼠單側輸尿管結紮誘導腎臟纖維化的單細胞轉錄體分析顯示，Ddr1 與受傷相關的中間型纖維母細胞狀態有關。在體外實驗中，TGF–β1 會增加腎臟纖維母細胞(NRK–49F)的 DDR1 表現；然而，Ddr1 基因敲落並未抑制 TGF–β1誘導纖維母細胞活化。相反地，DDR1 缺失降低細胞鋪展、黏著班(focal adhesion)形成及應力纖維(stress fiber)組成，同時促進類足體形成、膠原蛋白片段產生、降低膠原纖維硬度，並削弱 TGF–β1 誘導的膠原凝膠收縮。這些結果顯示，DDR1 促進細胞收縮力及收縮性膠原基質聚集，而 DDR1 表現降低則使纖維母細胞傾向於基質降解表型。
比較性細胞轉錄體分析顯示，非洲針刺鼠腎臟在單側輸尿管結紮誘導腎臟纖維化後仍會產生腎小管損傷，但相較於實驗室小鼠(Mus, C57BL/6)，其發炎、纖維化、代謝壓力及機械傳導相關基因的活化較弱。值得注意的是，Ddr1 在纖維化的 Mus 腎臟中被誘導，但在非洲針刺鼠中並未明顯上升。促纖維化路徑分析進一步顯示，非洲針刺鼠中 TGF–β、Notch、Wnt 及 NF–κB 訊號活化較低。綜合而言，這些結果顯示 DDR1 相關的膠原機械傳導降低，以及促纖維化發、反應受到限制，可能有助於非洲針刺鼠抗纖維化的腎臟修復能力。

Renal fibrosis is a common pathological feature of chronic kidney disease and is mainly driven by persistent fibroblast activation, extracellular matrix accumulation, and tissue stiffening. This study investigated the mechanobiological role of the collagen receptor DDR1 in renal fibroblasts and further explored the potential mechanisms underlying fibrosis–resistant renal repair in the regenerative mammal, the African spiny mouse (Acomys cahirinus).
Single–cell transcriptomic analysis of mouse kidneys with unilateral ureteral obstruction (UUO)–induced renal fibrosis showed that Ddr1 was associated with injury–related intermediate fibroblast states. In vitro, TGF–β1 increased DDR1 expression in renal fibroblasts (NRK–49F). However, Ddr1 knockdown did not suppress TGF–β1–induced fibroblast activation. Instead, DDR1 depletion reduced cell spreading, focal adhesion formation, and stress fiber organization, while promoting podosome–like structure formation, collagen fragmentation, reduced collagen fibril stiffness, and impaired TGF–β1–induced collagen gel contraction. These findings suggest that DDR1 promotes cellular contractility and contractile collagen matrix organization, whereas reduced DDR1 expression shifts fibroblasts toward a matrix–degrading phenotype.
Comparative transcriptomic analysis showed that Acomys kidneys still developed tubular injury after UUO–induced renal fibrosis. However, compared with laboratory mice (Mus, C57BL/6), Acomys exhibited weaker activation of inflammation–, fibrosis–, metabolic stress–, and mechanotransduction–associated genes. Notably, Ddr1 was induced in fibrotic Mus kidneys but was not markedly upregulated in Acomys kidneys. Pro–fibrotic pathway analysis further revealed attenuated activation of TGF–β, Notch, Wnt, and NF–κB signaling in Acomys. Taken together, these findings suggest that reduced DDR1–associated collagen mechanotransduction and restrained pro–fibrotic inflammatory responses may contribute to fibrosis–resistant renal repair in Acomys.

Abstract 2
摘要 4
誌謝 5
Table contents 12
Figure contents 13
Abbreviation 15
Chapter 1: Introduction 20
1 Chronic kidney disease and fibrosis as an irreversible endpoint 20
2 Cellular basis of renal fibrosis: fibroblast activation, heterogeneity, and plasticity 21
3 Mechanobiology in fibrosis: ECM stiffness and cell–matrix interaction 23
4 Cell–matrix interaction: collagen receptors as mechanosensory regulators of fibrosis 25
5 Discoidin domain receptor signaling in fibrosis and tissue remodeling 27
6 Regeneration across species: lessons from regenerative vertebrate models 28
7 Spiny mice as a mammalian model of scar–free regeneration 30
8 Rationale and the aim of this study 35
Chapter 2: Materials and Methods 36
1 Single–cell RNA–seq analysis 36
2 Cells and reagents 37
3 Establishment of stable knockdown cell lines 37
4 Western blotting 38
5 Immunofluorescence staining 39
6 Atomic force microscopy measurement of collagen fibril stiffness 39
7 Collagen aggregation assay 40
8 Gel contraction assay 40
9 Protein precipitation from conditioned medium 41
10 Polyacrylamide gel preparation 41
11 Quantification of podosomes and stress fibers 42
12 Animal experiments and UUO surgery 42
13 Bulk RNA–seq analysis of Mus and Acomys kidneys 43
Chapter 3: DDR1 modulates cytoskeletal remodeling and podosome formation in renal fibroblasts 43
Results
1 Single–cell transcriptomic profiling identifies fibroblast state transitions and state–associated Ddr1 expression during UUO progression 43
2 TGF–β1 induces DDR1 upregulation during fibroblast activation but DDR1 is dispensable for myofibroblast marker induction 46
3 DDR1 depletion promotes podosome formation and alters actin cytoskeletal organization 47
4 DDR1 depletion is associated with reduced focal adhesion maturation in podosome–positive fibroblasts 49
5 Matrix stiffness regulates DDR1 expression and podosome formation in renal fibroblasts 50
6 DDR1 depletion alters collagen matrix remodeling and reduces contractile matrix organization 51
7 Exploratory analysis of DDR1–associated signaling molecules does not identify a consistent downstream signaling pattern 53
8 Summary of chapter 2: DDR1 functions as a mechanoresponsive regulator of cytoskeletal remodeling and podosome formation in renal fibroblasts 55
Chapter 4: Attenuated pro–fibrotic and inflammatory responses in Acomys during UUO–induced renal injury 57
Results
1 Literature–based curation of fibrosis–associated signaling pathways in mouse renal injury models 58
2 Comparative pathway–level expression profiling reveals distinct injury responses between Mus and Acomys 60
3 Acomys exhibits attenuated activation of pro–fibrotic and NF–κB–associated inflammatory pathways after UUO 66
4 Acomys kidneys preserve renal architecture and limit inflammatory and collagen matrix remodeling after UUO 69
5 Acomys kidneys resist UUO–induced interstitial stiffening despite higher basal tissue stiffness 70
6 Acomys primary renal fibroblasts retain TGF–β1–induced collagen aggregation capacity 71
Chapter 5: Discussion 69
1 Clone–dependent effects of shDdr1 knockdown on cytoskeletal and matrix–remodeling phenotypes 72
2 DDR1 regulates the balance between contractile and matrix–degradative cytoskeletal states 74
3 DDR1 influences focal adhesion organization without consistent activation of canonical signaling pathways 74
4 DDR1 may modulate integrin–associated cytoskeletal remodeling rather than global integrin activation 75
5 Limited activation of morphogen signaling despite tubular injury in Acomys 76
6 Metabolic preservation may contribute to fibrosis–resistant renal repair in Acomys 76
7 Restricted inflammatory amplification and potential macrophage state differences in Acomys 77
8 Distinct basal and injury–induced tissue stiffness in Acomys kidneys 79
9 Limitations and future directions 81
Chapter 6: Summary  85
References 90
Figures 103
Tables 144
Curriculum Vitae 150
                                    

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