摘要
雄激素性脱发（androgenetic alopecia，AGA）是最常见的进行性脱发。目前，药物治疗是治疗AGA的主要方法，然而，药物治疗具有明显的副作用。干细胞具有组织修复和维持微环境稳态的作用，可为治疗AGA提供新策略。本文综述了AGA的发病机制，探讨了传统药物治疗的缺陷，同时论述了干细胞及干细胞衍生物在治疗AGA中的研究进展，以期全面反映干细胞治疗AGA的前景。
脱发分为瘢痕性脱发和非瘢痕性脱发，雄激素脱发（androgenetic alopecia，AGA）是瘢痕性脱发中最常见的类型。流行病学数据显示，约80%的男性和30%的女性在整个生命过程中存在着AGA的困扰，在不同国家或地区的发病率有着显著差
目前，AGA的一线治疗方法为局部涂抹米诺地尔和口服非那雄胺，然而这两种药物一般需要长期使用，从而造成药物耐受及其他副作用；并且在停药后容易恢复脱
头发是皮肤的附属物。一个毛发单位在结构上分为3个亚单位，即毛干、毛根和皮脂腺。在皮脂腺下方靠近外根鞘的“隆突”部位存在着干细胞库（
图1 毛囊结构图（A）和不同时期的毛囊特征（B
额头发际线呈“M”型衰退和头顶毛发变薄是男性型的AGA典型模式特征。该过程主要是由于Ⅱ型5α还原酶的表达差异造成的。这种酶主要存在于毛囊的内根鞘中，可以将睾酮转化为与雄激素受体具有更高亲和力的二氢睾酮（dihydrotesterone，DHT）。与枕部头皮不同，头顶部头皮的毛囊表达更多的Ⅱ型5α还原酶，进而对雄激素更敏
研究表明Wnt/β-catenin、TGF-β、BMP等信号通路以及多种细胞因子相互串扰调控着毛发的生长周期，在AGA发病过程中这些信号通路会受到影响（
图2 雄激素脱发中毛发生长的信号调
Wnt：无翼/集成蛋白；Frizzled：卷曲受体；LRP：低密度脂蛋白；R-spondin：重组脊柱蛋白；DKK-1：Dickkopf相关蛋白1；DHT：二氢睾酮；5α reductase：5α还原酶；Testosterone：睾酮；Akt：蛋白激酶B；Erk：细胞外调节激酶；Gsk3β：糖原合成激酶-3；β-catenin： β-连环蛋白；LEF/TCF：淋巴增强结合因子/转录因子；Gli1：Gli家族锌指蛋白1；Smads：smad家族蛋白；TGF-β：转化生长因子β；BMP：骨形态发生蛋白；EGFR：表皮生长因子受体；EGF：表皮生长因子；FGFR：成纤维细胞生长因子受体；FGF：成纤维细胞生长因子；shh：音猬因子蛋白；SMO：平滑受体。（→：促进或激活；┤：抑制）
骨形态发生蛋白（bone morphogenetic protein，BMP）属于转化生长因子（transforming growth factor，TGF）超家族的一种分泌蛋白，主要参与毛囊干细胞的分化过程。BMP配体通过与特定的受体相互作用发挥生物活性。研究发现BMP的拮抗剂Noggin与BMP蛋白受体竞争性结合，可调节毛囊干细胞的增殖与分化。Noggin由间充质细胞分泌和表达，可诱导胚胎中的毛囊形态发生。Noggin活性在毛囊生长期逐渐增加，在静止期减弱，表明Noggin表达随毛发生长周期变化而变
细胞因子的调控在毛发生长中起着关键作用，例如血管内皮生长因子（vascular endothelial growth factor VEGF）、成纤维细胞生长因子（fibroblast growth factor，FGF）、血小板衍生生长因子（platelet derived growth factor，PDGF）等。体外研究表明，干细胞对血管和毛囊生长的促进作用与这些营养因子的分泌密切相关。营养因子可以促进毛发生长时毛囊周围血管形成，增加毛乳头细胞和毛囊的大小从而加速毛发的生长。临床已经证实，在AGA患者头皮中，VEGF的表达受阻，因此毛发不能正常生
目前，美国食品药品监督管理局（FDA）批准的临床上用于治疗雄激素的药物为非那雄胺和米诺地
| 药物/疗法 | 机 制 | 副作用 |
|---|---|---|
| 米诺地尔 | 血管扩张剂 | 接触性皮炎、多毛症 |
| 非那雄胺 | 5α还原酶抑制剂 | 性功能障碍、心理疾病 |
| 度他雄胺 | 5α还原酶抑制剂 | 性功能障碍 |
| 螺内酯 | 雄激素受体拮抗剂 | 高钾血症、月经紊乱 |
| 高浓度血小板血浆 | 生长因子促进头发生长 | 过敏、血肿 |
| 手术移植 | 头发再生 | 供体毛囊要求高 |
非那雄胺是Ⅱ型5α还原酶的抑制剂，通过降低血清和头皮中的DHT浓度，从而促进毛发生长；而米诺地尔则可扩张血管、诱导VEGF高表达，从而增加血管分布和对真皮乳头的营养供应以促进毛发生
1868年，德国著名生物学家Ernst Haeckel首次使用“干细胞”一词来描述具有自我更新和分化潜能的细胞，这些细胞能够分化为多个细胞谱系，是组织不断更新和再生的基础。根据来源的不同，可将干细胞分为胚胎干细胞和成体干细胞，而基于这些细胞的治疗统称为干细胞疗法。目前，用于干细胞疗法的干细胞大部分为成体干细胞，已经发现成体干细胞对多种疾病均具有显著疗效。这些作用一方面依赖于直接修复人体内受损伤的细胞或组
| 干细胞种类 | 临床试验NCT码 | 研究状态 |
|---|---|---|
| 脂肪来源间充质干细胞 | NCT03388840 | Ⅳ期临床 |
| 脂肪干细胞条件培养基 | NCT05296863 | Ⅲ期临床 |
| 基质血管组分（SVF） | NCT02865421 | Ⅱ期临床 |
| 毛囊真皮鞘细胞（毛囊干细胞） | NCT01286649 | Ⅱ期临床 |
| 脐带血间充质干细胞条件培养基 | NCT03676400 | 临床前研究 |
| 脂肪干细胞成分提取物 | NCT02594046 | 临床前研究 |
干细胞被认为是一种可行且安全的治疗方法。细胞来源、供体来源、产品生产和受体疾病状态是干细胞治疗的安全性和有效性相关的重要因
脂肪来源的间充质干细胞（adipose-derived stem cells，ADSCs）存在于皮下等脂肪组织中，较易获
毛乳头细胞位于毛囊底部向内凹陷的毛球中，属于真皮源性干细胞。毛乳头细胞可以刺激毛囊干细胞，调节毛发生长周
人脐带血间充质干细胞（human umbilical cord blood mesenchymal stem cells，hUCBMSCs）来源于新生儿的脐带组织，从脐带静脉血管中分离得
人的脐带血管包裹在胶状物质中，这种胶状物质称为华通氏胶。分离华通氏胶，经体外培养可获得间充质干细胞成为脐带间充质干细胞（human umbilical cord mesenchymal stem cells，hUCMSCs）。hUCMSCs较成体干细胞来源更加初始，免疫原性低、倍增时间短，且在获得时对人体不会带来任何伤害。目前hUCMSCs的使用不涉及任何道德伦理问
脱发是一种难以治疗的疾病，单独使用FDA批准的药物进行治疗往往伴随着较大的副作用和停药后复发。本文总结了可用的干细胞疗法，几乎所有的体内外实验均表现出干细胞治疗可改善脱发促进毛发生长，并且没有副作用，因此具有广阔的应用前景。干细胞治疗AGA的机制主要是通过旁分泌作用分泌细胞因子和生长因子，调节毛囊生长的微环境，从而调控毛发的生长。随着再生医学的探索，干细胞衍生的分泌蛋白（包括囊泡和外泌体）已成为治疗多种疾病的重要选择，它较干细胞直接治疗具有成本低，易于储存和运输等优势。但是目前将干细胞及干细胞的产品（细胞及细胞产品移植数量以及移植方法）运用于临床试验中缺乏一致性和标准化，这限制了研究结果的比较，这可能也限制了干细胞运用于临床研究的进步。这些疗法虽然存在着挑战和不确定性，但是它们在再生医学中的潜力是不可否认的，并且对该领域的影响仍然很大。因此，需要克服目前干细胞运用于临床的局限性以及障碍，结合新的技术以及研究改进干细胞在再生医学中使用合理性、有效性、规范性，从而推动再生医学的发展。
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