BACKGROUND Both pluripotent very small embryonic-like stem cells (VSELs) and induced pluripotent stem (iPS) cells were reported in 2006. In 2012, a Nobel Prize was awarded for iPS technology whereas even today the very existence of VSELs is not well accepted. The underlying reason is that VSELs exist in low numbers, remain dormant under homeostatic conditions, are very small in size and do not pellet down at 250-280g. The VSELs maintain life-long tissue homeostasis, serve as a backup pool for adult stem cells and are mobilized under stress conditions. An imbalance in VSELs function (uncontrolled proliferation) may result in cancer. SEARCH METHODS The electronic database 'Medline/Pubmed' was systematically searched with the subject heading term 'very small embryonic-like stem cells'. OBJECTIVE AND RATIONALE The most primitive stem cells that undergo asymmetric cell divisions to self-renew and give rise to progenitors still remain elusive in the hematopoietic system and testes, while the presence of stem cells in ovary is still being debated. We propose to review the available literature on VSELs, the methods of their isolation and characterization, their ontogeny, how they compare with embryonic stem (ES) cells, primordial germ cells (PGCs) and iPS cells, and their role in maintaining tissue homeostasis. The review includes a look ahead on how VSELs will result in paradigm shifts in basic reproductive biology. OUTCOMES Adult tissue-specific stem cells including hematopoietic, spermatogonial, ovarian and mesenchymal stem cells have good proliferation potential and are indeed committed progenitors (with cytoplasmic OCT-4), which arise by asymmetric cell divisions of pluripotent VSELs (with nuclear OCT-4). VSELs are the most primitive stem cells and postulated to be an overlapping population with the PGCs. Rather than migrating only to the gonads, PGCs migrate and survive in various adult body organs throughout life as VSELs. VSELs express both pluripotent and PGC-specific markers and are epigenetically and developmentally more mature compared with ES cells obtained from the inner cell mass of a blastocyst-stage embryo. As a result, VSELs readily differentiate into three embryonic germ layers and spontaneously give rise to both sperm and oocytes in vitro. Like PGCs, VSELs do not divide readily in culture, nor produce teratoma or integrate in the developing embryo. But this property of being relatively quiescent allows endogenous VSELs to survive various kinds of toxic insults. VSELs that survive oncotherapy can be targeted to induce endogenous regeneration of non-functional gonads. Transplanting healthy niche (mesenchymal) cells have resulted in improved gonadal function and live births. WIDER IMPLICATIONS Being quiescent, VSELs possibly do not accumulate genomic (nuclear or mitochondrial) mutations and thus may be ideal endogenous, pluripotent stem cell candidates for regenerative and reproductive medicine. The presence of VSELs in adult gonads and the fact that they survive oncotherapy may obviate the need to bank gonadal tissue for fertility preservation prior to oncotherapy. VSELs and their ability to undergo spermatogenesis/neo-oogenesis in the presence of a healthy niche will help identify newer strategies toward fertility restoration in cancer survivors, delaying menopause and also enabling aged mothers to have better quality eggs.

中文翻译：

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内源性，非常小的胚胎样干细胞：严格的综述，治疗潜力和前瞻性。

背景技术在2006年，报告了多能非常小的胚胎样干细胞（VSEL）和诱导性多能干（iPS）细胞。2012年，iPS技术获得了诺贝尔奖，而即使在今天，VSEL的存在仍未得到很好的认可。根本原因是VSEL数量少，在稳态条件下保持休眠，尺寸很小，在250-280g时不会沉淀下来。VSEL​​维持终生的组织动态平衡，充当成人干细胞的备用池，并在压力条件下动员起来。VSEL​​s功能失衡（增殖失控）可能导致癌症。搜索方法使用主题词“非常小的胚胎样干细胞”系统搜索“ Medline / Pubmed”电子数据库。目的和理由经历不对称细胞分裂以自我更新并产生祖细胞的大多数原始干细胞在造血系统和睾丸中仍然难以捉摸，而卵巢中干细胞的存在仍在争论中。我们建议回顾有关VSEL，其分离和表征方法，其个体发育，它们与胚胎干细胞（ES），原始生殖细胞（PGC）和iPS细胞的比较及其在维持组织稳态中的作用的现有文献。审查包括对VSEL如何导致基本生殖生物学范式转变的展望。结果成人组织特异性干细胞，包括造血，精原细胞，卵巢和间充质干细胞，具有良好的增殖潜力，并且确实是祖细胞（具有细胞质OCT-4），它是由多能VSEL（带有核OCT-4）的不对称细胞分裂引起的。VSEL​​是最原始的干细胞，并假定是与PGC重叠的种群。PGC不仅可以迁移到性腺，还可以作为VSEL在整个生命中的各种成年人体器官中迁移和生存。VSEL​​s表达多能性和PGC特异性标记，并且与从胚泡期胚胎的内部细胞团获得的ES细胞相比，在表观遗传和发育上更加成熟。结果，VSEL容易分化为三个胚芽层，并在体外自发产生精子和卵母细胞。像PGC一样，VSEL在培养中不易分裂，也不产生畸胎瘤或整合到发育中的胚胎中。但是这种相对静止的特性使内源性VSEL能够幸免于各种有毒的伤害。在肿瘤治疗中存活的VSEL可以靶向诱导非功能性腺的内源性再生。移植健康的利基（间质）细胞可改善性腺功能和活产。对小鼠的影响静止状态下，VSEL可能不会积累基因组（核或线粒体）突变，因此可能是再生和生殖医学的理想内源性，多能干细胞候选者。成人性腺中存在VSEL及其在癌治疗中存活的事实可能消除了在癌治疗之前将性腺组织堆积以保留生育力的需要。