Prospectively Isolated Human Bone Marrow Cell-Derived MSCs Support Primitive Human CD34-Negative Hematopoietic Stem Cells

Abstract

Hematopoietic stem cells (HSCs) are maintained in a specialized bone marrow (BM) niche, which consists of osteoblasts, endothelial cells, and a variety of mesenchymal stem/stromal cells (MSCs).However, precisely what types of MSCs support human HSCs in the BM remain to be elucidated because of their heterogeneity. In this study, we succeeded in prospectively isolating/establishing three types of MSCs from human BM-derived lineage-and CD45-negative cells, according to their cell surface expression of CD271 and stage-specific embryonic antigen (SSEA)24. Among them, the MSCs established from the Lineage1 SSEA-4 1 fraction (DP MSC) could differentiate into osteoblasts and chondrocytes, but they lacked adipogenic differentiation potential. The DP MSCs expressed significantly higher levels of well-characterized HSC-supportive genes, including IGF-2, Wnt3a, Jagged1, TGFb3, nestin, CXCL12, and Foxc1, compared with other MSCs. Interestingly, these osteo-chondrogenic DP MSCs possessed the ability to support cord blood-derived primitive human CD34-negative severe combined immunodeficiency-repopulating cells. The HSCsupportive actions of DP MSCs were partially carried out by soluble factors, including IGF-2, Wnt3a, and Jagged1. Moreover, contact between DP MSCs and CD34-positive (CD34 1 ) as well as CD34-negative (CD34 2 ) HSCs was important for the support/maintenance of the CD34 1/2 HSCs in vitro. These data suggest that DP MSCs might play an important role in the maintenance of human primitive HSCs in the BM niche. Therefore, the establishment of DP MSCs provides a new tool for the elucidation of the human HSC/niche interaction in vitro as well as in vivo. STEM CELLS 2015;33:1554-1565

Impact of osteoblast maturation on their paracrine growth enhancing activity on cord blood progenitors

“…Recent studies have shown that phenotypically defined fresh human BM MSC subpopulations (eg CD271 + CD140a low/− or CD271 +/− SSEA-4 − ) can support in coculture the growth repopulating potential of human HSC. 40,41 Herein, we favoured the use of culturederived BM MSC to study the correlation between osteogenic differentiation and maturation on the capacity of the feeder cells to support haematopoiesis. Our study demonstrates that the capacity of OCM to promote the growth of CB CD34 + cells and progenitors (CFC, LTC-IC)…”

Are nestin-positive mesenchymal stromal cells a better source of cells for CNS repair?

“…Moreover, the various subtypes of MSCs that make up the BM niche (illustrated in Fig. 3) have been mainly identified from rodent studies, and it is yet not known if similar cells exist in the human BM; although several recent reports have shown that the human BM niche contains nestin-positive MSCs (Crisan et al., 2008, Matsuoka et al., 2015, Pacini and Petrini, 2014, Schajnovitz et al., 2011). These data corroborate our own published results which demonstrate that around 50% of purified BM-MSC express nestin immunoreactivity (Johnstone et al., 2015).…”

SOST, an LNGFR target, inhibits the osteogenic differentiation of rat ectomesenchymal stem cells

“…Previous reports have shown that LNGFR is involved in cell death and axonal degeneration in response to injury . Increasing numbers of studies have demonstrated that LNGFR can serve as a cell surface marker for mesenchymal stem cells (MSCs) and that LNGFR‐positive MSCs present increased potential for osteogenesis . In this study, EMSCs were isolated from embryonic facial processes and sorted to obtain LNGFR + EMSCs and LNGFR − EMSCs.…”

“…12 Increasing numbers of studies have demonstrated that LNGFR can serve as a cell surface marker for mesenchymal stem cells (MSCs) and that LNGFR-positive MSCs present increased potential for osteogenesis. [13][14][15][16][17][18] In this study, EMSCs were isolated from embryonic facial processes and sorted to obtain LNGFR + EMSCs and LNGFR − EMSCs. We further demonstrated that LNGFR + EMSCs had a higher osteogenic capacity and lower SOST levels compared with LNGFR − EMSCs and that SOST negatively regulated the osteogenic differentiation of EMSCs.…”