Mouse Bone Marrow VSELs Exhibit Differentiation into Three Embryonic Germ Lineages and Germ & Hematopoietic Cells in Culture

Abstract

Very small embryonic-like stem cells (VSELs) have been reported in various adult tissues, express pluripotent and primordial germ cells (PGCs) specific markers, are mobilized under stress/disease conditions, give rise to tissue committed progenitors and thus help regenerate and maintain homeostasis. The aim of the present study was to evaluate in vitro differentiation potential of VSELs using a quantitative approach. VSELs were collected from mouse bone marrow after 4 days of 5-fluorouracil (5-FU, 150 mg/Kg) treatment, further enriched by size based filtration and cultured on a feeder support in the presence of specific differentiation media. Cultured VSELs were found to differentiate into all three embryonic germ cell lineages, germ and hematopoietic cells after 14 days in culture. This was confirmed by studying Nestin, PDX-1, NKX2.5, DAZL, CD45 and other markers expression by various approaches. Very small, CD45 negative cells collected and enriched from GFP positive 5-FU treated mice bone marrow transitioned into CD45 positive cells in vitro thus demonstrating that VSELs can give rise to hematopoietic stem cells (HSCs). We envision that VSELs may be responsible for plasticity and ability of bone marrow cells to give rise to non-hematopoietic tissue progenitors of all 3 germ layers. Moreover the ability of VSELs to differentiate into germ cells as well as all the three lineages provides further evidence to support their pluripotent state and confirms developmental link between bone marrow VSELs and PGCs. The property of quiescence, no risk of teratoma formation and autologus source, make pluripotent VSELs a potential candidate to facilitate endogenous regeneration compared to cell replacement strategy envisioned using embryonic and induced pluripotent stem cells.

Bone Marrow Very Small Embryonic-Like Stem Cells: New Generation of Autologous Cell Therapy Soon Ready for Prime Time?

“…In this issue of Stem Cell Reviews and Reports, Shaikh and colleagues [4] provide both potential mechanistic insights and clinically relevant informations about VSELs differentiation. Indeed, they demonstrate for the first time in a single study that mouse bone marrow, after a 5FU treatment, was enriched in VSELs that underwent multi-lineage differentiation.…”

Prolonged Growth Hormone/Insulin/Insulin-like Growth Factor Nutrient Response Signaling Pathway as a Silent Killer of Stem Cells and a Culprit in Aging

“…The proximal part of the epiblast also gives rise to primordial germ cells (PGCs), which, as precursors of gametes, carry developmental totipotency to the next generation [3]. As it will be discussed later in this review, we and others have identified a population of very small embryonic-like stem cells (VSELs) in postnatal tissues that share several characteristics with migrating PGCs [4–21]. The number of these cells in adult tissues seems to correlate positively with life span, and VSELs are proposed as a backup population for TCSCs in adult life [22–25].…”

Why are hematopoietic stem cells so ‘sexy’? on a search for developmental explanation

“…25 Finally, in a very recent study murine BM-derived VSELs have been demonstrated to differentiate into germline cells. 18 Below, I will discuss the potential developmental link between PGCs and hematopoiesis.…”