Closing the circle of germline and stem cells: the Primordial Stem Cell hypothesis

Abstract

Background: Germline determination is believed to occur by either preformation or epigenesis. Animals that undergo germ cell specification by preformation have a continuous germline. However, animals with germline determination by epigenesis have a discontinuous germline, with somatic cells intercalated. This vision is contrary to August Weismann's Germ Plasm Theory and has led to several controversies. Recent data from metazoans as diverse as planarians, annelids and sea urchins reveal the presence of pluripotent stem cell populations that express germ plasm components, despite being considered to be somatic. These data also show that germ plasm is continuous in some of these animals, despite their discontinuous germline.

Presentation of the hypothesis: Here, based on recent molecular data on germ plasm components, I revise the germline concept. I introduce the concept of primordial stem cells, which are evolutionarily conserved stem cells that carry germ plasm components from the zygote to the germ cells. These cells, delineated by the classic concept of the Weismann barrier, can contribute to different extents to somatic tissues or be present in a rudimentary state. The primordial stem cells are a part of the germline that can drive asexual reproduction.

Testing the hypothesis: Molecular information on the expression of germ plasm components is needed during early development of non-classic model organisms, with special attention to those capable of undergoing asexual reproduction and regeneration. The cell lineage of germ plasm component-containing cells will also shed light on their position with respect to the Weismann barrier. This information will help in understanding the germline and its associated stem cells across metazoan phylogeny.

Implications of the hypothesis: This revision of the germline concept explains the extensive similarities observed among stem cells and germline cells in a wide variety of animals, and predicts the expression of germ plasm components in many others. The life history of these animals can be simply explained by changes in the extent of self-renewal, proliferation and developmental potential of the primordial stem cells. The inclusion of the primordial stem cells as a part of the germline, therefore, solves many controversies and provides a continuous germline, just as originally envisaged by August Weismann.

Figure 1

The classical model of germline determination and its controversies. (A) Germline determination by preformation. The germ plasm present in the zygote is inherited by the primordial germ cells (PGCs) and not by the rest of the somatic cells derived from it. The PGCs give rise to germ cells (GCs) and these in turn to sperm and oocytes. Somatic cells cannot affect the germline, and, therefore, the Weismann barrier can be easily imagined in this model. Both germline continuity and germ plasm continuity are observed. (B) Germline determination by epigenesis. The zygote gives rise only to somatic cells, from which a subpopulation is specified by epigenetic signals to become the PGCs. The Weismann barrier is, therefore, broken by these somatic cells, and neither the germline nor the germ plasm is continuous. (C) In animals classically thought to follow the epigenesis model as diverse as annelids and sea urchins germ plasm components are found in the zygote and inherited by cells with both somatic and germ potential. These cells give rise to the PGCs but also to somatic tissues, and often have stem cell-like properties. The Weismann barrier is broken by these cells, since they are classically considered to be somatic. However, even though the germline is considered to be discontinuous, germ plasm continuity can be observed flowing from the zygote to these cells and forth to the PGCs. (A-C) Germ plasm component expression is depicted in red-magenta colors and green dots. z, zygote; pgc, primordial germ cells; gc, germ cells; oc, oocyte; sc, somatic cell.

Figure 2

The germline cycle in freshwater planarians. Freshwater planarians possess a population of stem cells, the so called neoblasts, which represents the PriSCs in these organisms (PriSC). Neoblasts are able to give rise to the GCs (gc) and to somatic cells (sc). GCs give rise to oocytes (oc) and sperm (s), which jointly give rise to the zygote (z). The zygote gives rise to both somatic cells and the PriSCs. The planarian PriSCs have unlimited self-renewal (sr) and both germ potential (gp) and somatic potential (sp). Green dots represent the presence of nuage granules and germ plasm components. The dotted blue line represents the position of the germ-to-soma boundary, as classically understood. The dotted red line represents the proposed position of the germ-to-soma boundary as postulated in the Primordial Stem Cells hypothesis, which coincides with the Weismann barrier (solid black line) in freshwater planarians. PriSCs, primordial stem cells.

Figure 3

Germ plasm components expression in lophotrochozoans and their germline cycles. (A-C) Schematic of Schmidtea polychroa (A), Platynereis dumerilii (B) and Crassostrea gigas (C). (A) The cleaving blastomeres of S. polychroa express germ plasm components and likely give rise to the embryonic cells. These cells are believed to give rise to the neoblasts, but also to GCs and somatic tissues. (B) A putative germ plasm is found in the zygote of P. dumerilii and inherited by the 4d blastomere, which generates the PGCs but also the MPGZ, a germ plasm component-containing proliferative tissue with somatic potential (C) The early embryonic development of C. gigas is similar to that of P. dumerilii. However, only 2 cells derived from the 4d blastomere still show germ plasm components: they are believed to be the PGCs and become quiescent until later stages. (D-F) Modes of germline cycle in S. polychroa (D), P. dumerilii (E) and C. gigas (F). (D) Unlimited PriSCs: the zygote in S. polychroa gives rise to a population of stem cells (the PriSCs) with self-renewal (sr) and both somatic (sp) and germ potential (gp). (E) Restricted PriSCs: In P. dumerilii the 4d lineage is a population of pluripotent stem cells with both somatic (sp) and germ potential (gp) with more restricted self-renewal. (F) Rudimentary PriSCs: The germ plasm-containing cells of C. gigas only retain dual germ/soma potential for a few divisions and only the PGCs retain germ plasm components. Dotted red lines depict the proposed germ-to-soma boundary. GCs, germ cells; MPGZ, mesodermal posterior growth zone; PGCs, primordial germ cells; PriSCs, primordial stem cells.

Figure 4

The PriSCs of Caenorhabditis elegans. Schematic of C. elegans early development. The zygote (P₀) gives rise to the somatic AB cell and the series of germline blastomeres (P₁, P₂, P₃ and P₄), which retain the P granules (green dots). Each of them has both somatic and germ potential and divides to give rise to one somatic cell and another germline cell, except P₄, which only has germ potential and can, therefore, be called PGC. P₄ arises from the division of the presumptive primordial germ cell (P3, pPGC), and gives rise to the PGCs Z2 and Z3, which will remain silent during development and later proliferate to give rise to the GCs. Therefore, P₁ to P₃ are the rudimentary PriSCs of C. elegans. The sizes and shapes of cells are purely schematic and do not represent their actual shapes and relative sizes. PGCs, primordial germ cells; PriSCs, primordial stem cells.

Figure 5

Asexual and sexual germlines. (A) Animals capable of both sexual and asexual reproduction possess an asexual germline and a sexual germline. (B) Animals that reproduce exclusively asexually have nonetheless an asexual germline, which resides in the PriSCs. (C) Animals that exclusively reproduce sexually have lost the self-renewing capacities and/or somatic potential of their PriSCs and, therefore, only a classical sexual germline is present. PriSCs, primordial stem cells.

Figure 6

The germ-to-soma boundary according to the classical view and the PriSC hypothesis. (A-C) The dotted blue and red lines depict the classical and the proposed germ-to-soma boundary respectively. The black line depicts the Weismann barrier. Green arrows depict the origin of new generations. Green boxes indicate the source of contributions to forthcoming generations. (A) In animals with unlimited PriSCs these are classically considered to be somatic, breaking the germline continuity. The proposed germ-to-soma boundary makes both germline and germ plasm continuous and consistent with the Weismann barrier. New generations originate by sexual reproduction (large green arrow) or by asexual reproduction (small green arrow). The PriSCs contribute to forthcoming generations by enabling regeneration after asexual division, by embryonically generating the GCs or by regenerating GCs if these are lost. (B) In animals with restricted PriSCs the classical germ-to-soma boundary has to separate the PriSCs according to their germ or somatic potential and similarly breaks the germline continuity. The proposed germ-to-soma boundary again makes both germline and germ plasm continuous and consistent with the Weismann barrier. New generations originate only by sexual reproduction and the PriSCs only contribute to forthcoming generations by generating GCs. It is still unclear if PriSCs can regenerate GCs if lost (question mark). (C) In animals with rudimentary PriSCs the classical germ-to-soma boundary coincides with the proposed germ-to-soma boundary and the Weismann barrier, with both a continuous germline and germ plasm. New generations originate only by sexual reproduction and the PriSCs only contribute to forthcoming generations by generating PGCs. GCs, germ cells; PGCs, primordial germ cells; PriSCs, primordial stem cells.