[導讀高分期刊] 幹細胞的治療對人類疾病的應用

本文參考自以下 SCI 高分期刊論文

Stem cell-based therapy for human diseases. Sig Transduct Target Ther 7, 272 (2022). https://doi.org/10.1038/s41392-022-01134-4 ( Impact factor ~ 41 ,2023 )

幹細胞療法的潛力

幹細胞療法在應對傳統治療無法解決的疾病和障礙中的關鍵作用。特別是人類多能幹細胞（hPSCs）和間質幹細胞（MSCs），它們是再生醫學的基礎。這些療法不僅旨在管理疾病，還致力於通過激發人體的自然修復機制，恢復組織功能。

本文回顧了癌症免疫療法和歐洲MSC療法的成功，並將幹細胞療法定位為一個新興領域，對於目前無法治癒的疾病具有巨大潛力。然而，也提到了未經證實的療法和未受監管的診所濫用幹細胞的危險，這導致了公共安全方面的擔憂。

幹細胞類型：分化與潛能

人類多能幹細胞（hPSCs）

hPSCs具有分化為來自三個胚層的任何細胞類型的能力，這使它們在再生醫學中特別有潛力。然而，由於倫理問題和使用胚胎幹細胞（ESCs）帶來的免疫排斥風險，進展受到了一定限制。本文指出了誘導多能幹細胞（iPSCs）的進展，這些細胞通過重編程體細胞進入多能狀態，從而繞過了倫理問題。

• 臨床潛力：hPSCs已被測試用於治療心血管疾病、視網膜變性和脊髓損傷，儘管結果令人鼓舞，但其使用的可擴展性和安全性仍面臨挑戰。

間質幹細胞（MSCs）

MSCs是多能的，能夠分化為例如骨細胞、軟骨細胞和脂肪細胞。它們主要來源於骨髓（BM）、脂肪組織（AT）和臍帶（UC）。由於它們的免疫調節性，MSCs風險較低，且在臨床試驗中相對安全。

• 臨床潛力：MSCs被用來治療神經系統疾病、心血管疾病和自身免疫性疾病。它們在調節免疫反應和促進組織修復方面展現了顯著的潛力。

幹細胞的臨床應用

神經系統疾病

本文探討了BM-MSCs在治療神經系統疾病如中風、脊髓損傷、腦性麻痺和多發性硬化症中的應用。MSCs已顯示出調節免疫系統、減少炎症和促進神經再生的潛力。然而，儘管早期試驗顯示出希望，但仍需要更多的長期設計良好的試驗來最終證明其療效。

BM-MSCs 的主要優勢包括它們能夠遷移到損傷部位，影響免疫環境，並創造再生微環境。臨床試驗表明，脊髓損傷患者的運動功能有所改善，並且中風損害有所減少。

肺部疾病

幹細胞療法，特別是使用UC-MSCs，正在被用於治療急性呼吸窘迫綜合徵（ARDS）等肺部疾病。MSCs 在肺部疾病中的治療益處與其調節免疫反應和減少炎症的能力有關，從而促進肺部更快康復。然而，本文強調許多臨床試驗結果不一致，這表明需要改進劑量、時間和給藥途徑以實現最佳結果。

UC-MSCs 在肺部應用中的優勢在於它們的非侵入性採集、低免疫原性和高增殖率。這些特性使它們成為肺部疾病治療的理想選擇，儘管仍需更多強有力的臨床證據來確定其長期安全性和有效性。

心血管疾病

幹細胞療法在心臟病治療中的應用已有十多年，重點是修復受損的心臟組織。本文討論了臨床試驗中顯示出的矛盾結果：儘管一些臨床前試驗顯示心臟功能顯著改善，但III期臨床試驗尚未一致地顯示出臨床益處，如增加心肌收縮力或減小梗塞大小。

結果表明，細胞可能不直接參與組織再生，而是通過調節免疫反應和減少纖維化發揮作用。文章指出，細胞準備、給藥方法和患者選擇等因素在確定這些療法的有效性中起著至關重要的作用。

代謝/內分泌疾病

對於代謝疾病如糖尿病，幹細胞療法旨在恢復胰腺功能或減少受影響組織中的炎症反應。本文提到正在進行的關於MSCs如何在增強胰島素敏感性和恢復胰島β細胞功能方面的研究，但強調臨床試驗仍處於早期階段，並且結果尚不一致。

生殖與皮膚疾病

MSCs，尤其是AT-MSCs，正在皮膚再生和生殖健康中進行測試。這些幹細胞因其抗炎特性和易於提取而具有優勢。本文強調，AT-MSCs在加速傷口癒合和促進受損皮膚的組織再生方面顯示出積極的結果。同樣，生殖應用集中於使用MSCs解決不孕不育問題並修復生殖組織的損傷。

本論文的核心假設：MSC來源與靶向療法

本文的核心命題是，來自不同組織的MSC可能更適合基於其來源的特定疾病治療：

• BM-MSCs：對於治療神經系統疾病，如腦損傷和脊髓損傷，可能更有效，因為它們在神經生成中的作用。
• AT-MSCs：理想用於皮膚再生和生殖疾病，因為它們在脂肪組織中具有再生能力，並且脂肪組織參與這些系統的運作。
• UC-MSCs：適合治療肺部疾病和急性呼吸道病症，因為這些細胞具有強大的抗炎和免疫調節特性。

這一假設得到了多項臨床試驗的支持，這些試驗在不同的疾病模型中測試了不同來源的MSCs。本文呼籲進行更多的靶向研究，以驗證這一假設，並了解MSC在基於其組織來源的疾病治療中發揮的機制作用。

安全性問題與挑戰

腫瘤生成和倫理問題

儘管hPSCs具有巨大潛力，但它們也伴隨著腫瘤形成的風險，特別是在分化不受控制的情況下。這尤其是使用ESCs時的一個問題，因為ESCs來自胚胎，移植到患者體內後可能會引發免疫排斥。倫理問題也限制了ESCs在全球範圍內的廣泛應用。

標準化問題

該領域面臨的主要障礙之一是缺乏在幹細胞處理、給藥和監測方面的標準化。本文強調需要在細胞來源、劑量和給藥方式方面建立標準化協議。沒有標準化，臨床試驗的結果將繼續有所不同，使得難以為幹細胞療法制定明確的指南。

臨床結果不一

尤其是心血管疾病和肺部功能障礙方面的臨床試驗結果不一。儘管有些研究報告了積極效果，但另一些研究未能顯示出顯著的臨床益處。作者認為，這些不一致可能是由於患者選擇、細胞劑量和治療方案之間的差異所致。未來的重點應放在優化這些變量上，以提高幹細胞療法的有效性。

結論：邁向靶向幹細胞療法

結論強調，儘管幹細胞療法顯示出巨大潛力，但在它們成為主流治療之前仍有很長的路要走。需要更多的研究來了解不同幹細胞類型的特定作用，並且必須進行多中心臨床試驗來驗證療法的有效性。

作者建議，專注於組織來源假說可能有助於個性化治療，使未來的療法更加精準和有效。特別是，本文呼籲更深入地了解來自不同組織的MSCs如何與它們的相關疾病環境相互作用的機制。

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1. Introduction: The Potential of Stem Cell Therapies

The introduction emphasizes the pivotal role of stem cell-based therapies in addressing diseases and disorders that traditional treatments have failed to cure. Stem cells, particularly human pluripotent stem cells (hPSCs) and mesenchymal stem cells (MSCs), are highlighted as the foundation for regenerative medicine. These therapies aim not just to manage diseases but to actively stimulate the body’s natural repair mechanisms and restore tissue functionality.

The paper reflects on the growing success of cancer immunotherapies and MSC-based therapies, particularly in Europe, framing stem cell-based therapies as an emerging field with immense potential for diseases that are currently incurable. However, it also discusses the dangers of unproven therapies offered by unregulated clinics that misuse stem cells, leading to public safety concerns.

2. Stem Cell Types: Differentiation and Potency

Human Pluripotent Stem Cells (hPSCs):

• hPSCs have the ability to differentiate into any cell type from the three germ layers, making them particularly versatile in regenerative medicine. Their potential is vast, but ethical concerns and the risk of immune rejection when using embryonic stem cells (ESCs) have slowed progress. The paper notes advancements in the use of induced pluripotent stem cells (iPSCs), which bypass these ethical concerns by reprogramming somatic cells into pluripotent states.
• Clinical Potential: hPSCs have been tested for cardiovascular diseases, retinal degeneration, and spinal cord injuries, with promising results but lingering challenges around the scalability and safety of their use.

Mesenchymal Stem Cells (MSCs):

• MSCs are multipotent, able to differentiate into cells like osteocytes, chondrocytes, and adipocytes. They are primarily sourced from bone marrow (BM), adipose tissue (AT), and umbilical cord (UC). MSCs are favored for their immunomodulatory properties, lower risk of immune rejection, and relatively safe profile in clinical trials.
• Clinical Potential: MSCs are being used to treat neurological disorders, cardiovascular conditions, and autoimmune diseases. They show significant promise in modulating immune responses and promoting tissue repair.

3. Clinical Applications of Stem Cells

Neurological Disorders:

The review explores the use of BM-MSCs in treating neurological disorders like stroke, spinal cord injuries, cerebral palsy, and multiple sclerosis. MSCs have shown potential to modulate the immune system, reduce inflammation, and promote neuroregeneration. However, the paper notes that while early trials show promise, more long-term, well-designed trials are needed to definitively prove efficacy.

The major advantages of BM-MSCs include their ability to migrate to injury sites, influence the immune environment, and create a regenerative microenvironment. Clinical trials have demonstrated improved motor function in spinal cord injury patients and reduced stroke damage.

Pulmonary Diseases:

Stem cell-based therapies, especially using UC-MSCs, are being explored for treating acute respiratory distress syndrome (ARDS) and other pulmonary conditions. The therapeutic benefit of MSCs in pulmonary diseases is linked to their ability to modulate the immune response and reduce inflammation, leading to faster lung recovery. However, the paper stresses that many clinical trials have shown conflicting results, indicating the need to refine dosing, timing, and delivery routes for optimal outcomes.

UC-MSCs are particularly advantageous in pulmonary applications due to their non-invasive harvesting, low immunogenicity, and high proliferation rate. These properties make them attractive for lung disease treatments, though more robust clinical evidence is still required to establish long-term safety and efficacy.

Cardiovascular Diseases:

Stem cell therapies for heart disease have been explored for over a decade, focusing on repairing damaged cardiac tissue. The paper discusses the paradoxical results in clinical trials: while some preclinical trials showed significant improvements in heart function, phase III trials have not consistently demonstrated clinical benefits such as increased myocardial contractility or reduced infarct size.

The results suggest that the cells may not directly contribute to tissue regeneration, but instead, modulate the immune response and reduce fibrosis. The paper points out that factors such as optimal cell preparation, delivery method, and patient selection play a crucial role in determining the effectiveness of these therapies.

Metabolic/Endocrine Disorders:

For metabolic diseases like diabetes, stem cell therapies aim to restore pancreatic function or reduce the inflammatory response in affected tissues. The paper mentions ongoing research into MSCs’ role in enhancing insulin sensitivity and restoring pancreatic beta-cell function, but it stresses that clinical trials are in early stages and have produced mixed results.

Reproductive and Skin Disorders:

MSCs, especially AT-MSCs, are being tested in skin regeneration and reproductive health. These stem cells are advantageous because of their anti-inflammatory properties and ease of extraction. The paper highlights that AT-MSCs have shown positive results in accelerating wound healing and promoting tissue regeneration in damaged skin. Similarly, reproductive applications focus on using MSCs to address infertility and repair damage in reproductive tissues.

4. Hypothesis: MSC Origin and Targeted Therapies

A core proposition of the paper is the hypothesis that MSCs derived from different tissues may be more suited to specific disease treatments based on their origin:

• BM-MSCs: More effective for treating neurological disorders, such as brain injuries and spinal cord injuries, because of their influence on neurogenesis and their ability to reach the central nervous system.
• AT-MSCs: Ideal for skin regeneration and reproductive disorders, due to their regenerative capabilities and their ability to thrive in adipose tissues, which are involved in these systems.
• UC-MSCs: Suited for treating pulmonary diseases and acute respiratory conditions, since these cells possess strong anti-inflammatory and immune-regulatory properties.

This hypothesis is supported by a review of clinical trials where different MSC sources have been tested in varied disease models. The paper calls for more targeted research to validate this hypothesis and to understand the mechanistic roles that MSCs play based on their tissue origin.

5. Safety Concerns and Challenges

Tumorigenicity and Ethical Concerns:

While hPSCs hold great promise, they come with the risk of tumorigenesis, especially if differentiation is not well-controlled. This is particularly a concern with ESCs, which are derived from embryos and may cause immune rejection when transplanted into patients. Ethical concerns also limit the widespread use of ESCs in many parts of the world.

Standardization Issues:

One of the major hurdles in the field is the lack of standardization in how stem cells are processed, administered, and monitored. The paper emphasizes the need for standardized protocols in terms of cell sourcing, dose, and delivery method. Without standardization, the results of clinical trials will continue to vary, making it difficult to establish clear guidelines for stem cell therapies.

Mixed Clinical Outcomes:

Clinical trials, particularly in cardiovascular diseases and pulmonary dysfunctions, have shown inconsistent results. While some studies report positive effects, others fail to show significant clinical benefits. The authors argue that these inconsistencies likely result from variations in patient selection, cell dose, and treatment protocols. A large part of the future focus should be on optimizing these variables to improve the efficacy of stem cell therapies.

6. Conclusion: Moving Toward Targeted Stem Cell Therapies

The conclusion emphasizes that while stem cell therapies have shown immense potential, there is still a long way to go before they become mainstream treatments. More research is needed to understand the specific roles of different stem cell types, and multicenter clinical trials must be conducted to validate the effectiveness of therapies.

The authors suggest that focusing on tissue-origin hypotheses may help personalize treatments for various diseases, allowing for more targeted and effective therapies in the future. In particular, the paper calls for a deeper understanding of the mechanisms by which MSCs derived from different tissues interact with their respective disease environments.

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