心血管疾病長期位居全球死亡原因之首，嚴重威脅人類健康。心肌梗塞後，心臟組織無法有效再生，是導致心臟衰竭、功能喪失的關鍵原因。傳統藥物治療雖能緩解症狀，卻無法從根本「修復」受損的心肌。中央研究院謝清河特聘研究員及其研究團隊，長期致力於心臟再生與轉譯醫學研究，結合跨領域技術，發展出具備高度技術移轉潛力的創新治療策略，為心臟功能重建帶來突破性曙光。

　　本團隊的核心研究策略可分為兩大方向：「細胞替代療法」與「環境優化策略」，兩者相輔相成，旨在建立完整的技術鏈結，加速轉譯為臨床產品。

核心技術一：全能幹細胞衍生心肌與內皮細胞共同移植技術

　　人類誘導多能幹細胞（induced pluripotent stem cell, iPSC）的出現，為再生醫學帶來了革命性的契機。謝清河團隊開發出高效能的分化與純化技術，能大量且穩定地產生具有功能性的人類心肌細胞（iPSC-cardiomyocyte）與內皮細胞（iPSC-endothelial cell）。研究顯示，將這兩種細胞進行特定比例的共同移植，能在心肌梗塞後產生顯著的協同效應。 

內皮細胞能有效促進心肌組織的血管化，改善受損區域的血液供應；而新植入的心肌細胞則能與原本的心臟組織整合，並促進心臟的收縮功能。此項技術不僅在小鼠實驗中得到證實，更在非人靈長類（nonhuman primate, NHP）恆河猴心肌梗塞模式中，顯著改善了心臟功能並減小了梗塞面積。此 NHP 模型之驗證結果，是國際首例、具備極高轉譯潛力、能直接銜接臨床試驗（first-in-human, FIH）的關鍵數據。本團隊正與生技業界積極發展相關之 GMP 生產流程與安全性驗證，旨在將其開發為「異體通用型」的細胞治療產品。 

核心技術二：腸道菌相調控與代謝物介入策略 

　　除了外源性的細胞替代，優化心臟本身的修復環境亦是關鍵。本團隊是全球首批證實「腸心軸（gut-heart axis）」在心肌梗塞修復中扮演重要角色的團隊之一。研究發現，腸道菌相失衡會影響心肌梗塞後的免疫反應與組織修復，而特定代謝物（如短鏈脂肪酸丁酸鹽butyrate）具有顯著的抗發炎與促進修復能力。 

基於此發現，本團隊發展出創新的代謝調控治療策略：藉由補充特定代謝物或調控腸道菌相（如 probiotics 或 prebiotics），能有效優化受損心肌的「微環境」，減少發炎並促進植入幹細胞的存活與整合。此項技術具備極高的產品開發價值，例如可用作幹細胞治療的佐劑、或是獨立開發為輔助心臟功能修復的代謝藥物或新一代益生菌產品（next-generation probiotics, NGPs）。

跨領域整合：奈米載體與長效藥物遞送系統 

　　為了解決外源性代謝物或藥物在體內半衰期短、難以精準作用於受損區域的難題，本團隊與奈米材料專家合作，開發出創新的藥物遞送系統。此系統利用具備心臟組織親和性的奈米載體，能精準、長效地將治療藥物釋放於梗塞區域。此技術不僅能優化代謝治療的療效，更有潛力應用於多種心臟治療藥物的精準遞送，相關奈米載體技術已完成初步專利佈局，具有與國際藥廠建立技術授權合作的龐大潛力。

結語與展望：建立台灣自主的生醫技術生態鏈 

　　謝清河團隊從心肌再生的基礎研究出發，結合 iPSC 細胞工程、代謝體學、腸道菌相調控以及奈米材料技術，逐步構築出完整的跨領域心臟修復技術。本團隊不僅已完成非人類靈長類模型的關鍵轉譯驗證，更致力於推動產學合作，旨在將研究成果轉化為臨床可用的產品。 

我們期待透過 TBF 平台，能進一步鏈結台灣的生技產業能量，加速本團隊核心技術（如 superdonor iPSC 與 metabolite delivery systems）之轉譯進程，為全球無數心血管疾病患者提供更有效、更根本的治療新選擇，並為台灣生醫產業在心臟再生領域，建立自主且具國際競爭力的技術鏈結。

（104年度TBF學術講座、中研院生物醫學科學研究所　謝清河特聘研究員）

From the Gut-Heart Axis to Stem Cell Regeneration: Next-Generation Therapeutic Strategies for Cardiovascular Diseases

II. Column Content

Cardiovascular disease remains the leading cause of mortality worldwide, posing a significant threat to human health. Following a myocardial infarction (MI, heart attack), the inherent regenerative capacity of the adult human heart is insufficient to repair the massive damage. While traditional pharmacological interventions can manage symptoms, they are unable to address the fundamental problem: the loss of functional myocardium, which leads to heart failure. At the Academia Sinica, the research team led by Distinguished Research Fellow Patrick C.H. Hsieh, MD, PhD, has dedicated years to cardiac regenerative medicine and translational science. By integrating interdisciplinary technologies, we are developing novel therapeutic strategies with high potential for technology transfer to achieve functional cardiac restoration.

Our team's core strategy is based on a dual-pronged approach: "Cell Replacement Therapy" and "Environmental Microenvironmental Optimization," which complement each other to create a robust translational pipeline for clinical product development. 

Core Technology 1: Co-Transplantation of iPSC-Derived Cardiomyocytes and Endothelial Cells

The advent of human Induced Pluripotent Stem Cells (iPSCs) has revolutionized regenerative medicine. Our team has developed highly efficient differentiation and purification protocols to produce stable, functional human cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) at scale. Our studies demonstrate that the specific co-transplantation of these two cell types creates a powerful synergistic effect post-MI.

The endothelial cells promote rapid and effective vascularization of the damaged tissue, restoring vital blood supply, maturing iPSC-CMs, while the newly implanted cardiomyocytes integrate with the native tissue, directly restoring the heart’s contractile function. This technology has been successfully validated not only in mouse models but, crucially, in non-human primate (NHP) models. The validation in NHP models provides the critical safety and efficacy data necessary to bridge the gap and secure a first-in-human clinical trial. In collaborations with the Taiwan bioindustry, we are actively finalizing the GMP manufacturing processes and safety studies with the goal of developing an "off-the-shelf" allogeneic cell therapy product. 

Core Technology 2: Gut Microbiota Modulation and Metabolic Intervention Strategies 

In addition to cellular replacement, optimizing the microenvironment within the damaged heart is equally essential for repair. Our team was among the first globally to provide definitive proof that the "gut-heart axis" plays a pivotal role in post-MI repair. We discovered that gut microbiota dysbiosis (imbalance) after MI dysregulates the systemic immune response. However, supplying specific microbial metabolites, such as the short-chain fatty acid butyrate, exerts potent anti-inflammatory effects and promotes myocardial repair. 

Based on this discovery, we have developed innovative metabolic regulation strategies. By supplementing specific metabolites or modulating the composition of the gut microbiota (e.g. through probiotics or prebiotics), we can effectively "prime" the microenvironment, reducing excessive inflammation and increasing the survival and integration of implanted stem cells. This approach holds significant product development value. These strategies can be developed as adjuvants to stem cell therapy, as standalone metabolic drugs to improve heart function, or as next-generation probiotic products.

Interdisciplinary Integration: Nano-Carriers for Sustained and Precise Drug Delivery

To address the challenge of the short half-life and poor bioavailability of therapeutic agents, such as butyrate, our team collaborated with nanotechnology experts to develop an innovative drug delivery system. This system utilizes nano-carriers engineered to have high affinity for ischemic cardiac tissue, enabling precise and sustained release of the therapeutic agent directly at the infarct zone. This technology not only optimizes the efficacy of metabolic interventions but has the potential to serve as a platform for the precise delivery of various other cardiovascular therapies. We have secured patent protection for this nano-carrier technology, which presents a significant opportunity for technology licensing and partnership with major pharmaceutical companies.

Conclusion and Outlook: Building an Autochthonous Biomedical Ecosystem for Taiwan

The Hsieh team follows a strategic translational pipeline that moves from fundamental biological discovery (e.g. the gut-heart axis) to complex engineering solutions (e.g. iPSC cell products, nano-carriers). We have achieved critical validation in NHP models and are deeply committed to promoting industry-academia collaborations to transform our research into clinical-grade products. 

We look forward to leveraging the TBF platform to link Taiwan's biomedical industry strengths with our core technologies (e.g. superdonor iPSC banking and metabolite delivery systems) to accelerate the translation process. Our ultimate goal is to provide millions of cardiovascular patients worldwide with a definitive and effective therapeutic option, thereby establishing an autochthonous, globally competitive technical link for Taiwan's biomedical sector in the field of cardiac regeneration.

(2015 TBF Chair in Biotechnology, Professor Ching-Ho Hsieh)