Germline stem cells in human

Abstract

The germline cells are essential for the propagation of human beings, thus essential for the survival of mankind. The germline stem cells, as a unique cell type, generate various states of germ stem cells and then differentiate into specialized cells, spermatozoa and ova, for producing offspring, while self-renew to generate more stem cells. Abnormal development of germline stem cells often causes severe diseases in humans, including infertility and cancer. Primordial germ cells (PGCs) first emerge during early embryonic development, migrate into the gentile ridge, and then join in the formation of gonads. In males, they differentiate into spermatogonial stem cells, which give rise to spermatozoa via meiosis from the onset of puberty, while in females, the female germline stem cells (FGSCs) retain stemness in the ovary and initiate meiosis to generate oocytes. Primordial germ cell-like cells (PGCLCs) can be induced in vitro from embryonic stem cells or induced pluripotent stem cells. In this review, we focus on current advances in these embryonic and adult germline stem cells, and the induced PGCLCs in humans, provide an overview of molecular mechanisms underlying the development and differentiation of the germline stem cells and outline their physiological functions, pathological implications, and clinical applications.

Fig. 1

History and main events of the studies in human germline stem cells. A glance of the discovery and advances starts from 1893 and the most of advances in human germline stem cells have been made since 2015

Fig. 2

Development of human embryos and the timing of hPGC specification. Human early embryos must obtain essential nourishment from mother by implantation into uterus, which occurs at the end of blastocyst stage. The Carnegie stages (CS) can be corresponding to days after fertilization or embryonic day (E). hPGCs are indicated in green (cytoplasm) and red (nucleus). The main parts of the figure were drawn by Figdraw

Fig. 3

Regulation network of hPGC specification. BMP- and WNT signaling promote the hPGCLC specification via regulating TFAP2C and SOX17. SOX17 is a critical regulator for hPGC specification and works upstream of BLIMP1. TFAP2C activates SOX17 expression. Final effects of hPGC specification promote germline development and pluripotency, while suppress somatic programs. The figure was drawn by Figdraw. Arrows and blunt-ended arrows depict positive and negative regulation, respectively. Dashed lines indicate synergetic role

Fig. 4

Extragonadal germ cell tumors (GCTs) in humans, related to PGC mismigration. As being pluripotential tumors, extragonadal germ cell tumors occur in a wide range of organs from central nervous system to ovary and testis indicated in the central panel, with expression of PGC markers, including PLAP, TFAP2C, NANOG, OCT4, SOX17, KIT, VASA, CXCR4, TSPY, MIC2, AMH, and MAGE-A4 listed in the right panel. Some elements of the figure were derived from Soehui

Fig. 5

Methodology of hPGCLCs induction. hPGCLCs are induced from both embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). a The iMeLCs strategy. b The 4i strategy. Induction culture timelines and added factors are indicated on the upper and the left in each panel, respectively

Fig. 6

Fertility preservation and treatment of infertility and cancer in humans. Germ cell/gonad tissue transplantation is an alternative therapeutic means for treating infertility, and it is also a promising treatment strategy for both pubertal and prepubertal boys/girls diagnosed with cancers who will suffer from irradiation and chemotherapy. Cell sources for transplantation could include germ stem cells and hPGCLCs. As new progress in cell induction, transplanted cells might come from somatic cells of patients, which can be induced into gametes via hPGCLCs in the future. Some parts of the figure were drawn by Figdraw