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Identification of a Distinct Small Cell Population from Human Bone Marrow Reveals Its Multipotency In Vivo and In Vitro

2014-01-17 14:00:22

Public Library of Science One; 2014 January 17; DOI: 10.1371/journal.pone.0085112



James Wang, Xiaoyu Guo, Monica Lui, Pei-Ju Chu, Jennifer Yoo, Megan Chang, Yun Yen



Abstract



Small stem cells, such as spore-like cells, blastomere-like stem cells (BLSCs), and very-small embryonic-like stem cells (VSELs) have been described in recent studies, although their multipotency in human tissues has not yet been confirmed. Here, we report the discovery of adult multipotent stem cells derived from human bone marrow, which we call StemBios (SB) cells. These isolated SB cells are smaller than 6 ìm and are DAPI+ and Lgr5+ (Leucine-Rich Repeat Containing G Protein-Coupled Receptor 5). Because Lgr5 has been characterized as a stem cell marker in the intestine, we hypothesized that SB cells may have a similar function. In vivo cell tracking assays confirmed that SB cells give rise to three types of cells, and in vitro studies demonstrated that SB cells cultured in proprietary media are able to grow to 6–25 ìm in size. Once the SB cells have attached to the wells, they differentiate into different cell lineages upon exposure to specific differentiation media. We are the first to demonstrate that stem cells smaller than 6 ìm can differentiate both in vivo and in vitro. In the future, we hope that SB cells will be used therapeutically to cure degenerative diseases.



Introduction



Stem cells have been derived from the inner cell mass (hESCs: human Embryonic Stem Cells), adult tissues, and adult somatic cells (iPSs: induced Pluripotent Stem Cells). Although hESCs and iPSs are capable of becoming almost any type of specialized cell in the body and may have the potential to generate replacement cells for a broad array of tissues and organs, future transplantations using these cells are hindered by immune rejection and teratoma formation. As a result, the search for multipotent or pluripotent stem cells from adult tissue has become increasingly important in stem cell research. Adult stem cells, unlike hESCs and iPSs, do not undergo teratoma formation or immune rejection in autologous transplants.



Currently, adult stem cell studies have focused on MSCs (mesenchymal stem cells), which are considered a promising therapeutic approach for many diseases. They can be isolated from sources such as umbilical cord blood and bone marrow, among others. However, plasticity of MSCs for trans-differentiation is questionable because they appear to differentiate into mesoderm lineages only. Thus, obtaining multipotent or pluripotent adult stem cells that can differentiate into different germ layers is crucial for future cell therapy.



The race to discover adult pluripotent stem cells began early this century. In 2002, Jiang et al. reported their findings on multipotent adult progenitor cells (MAPCs) from bone marrow that could differentiate into ectoderm, mesoderm, and endoderm cells, introducing a new avenue in the discovery of pluripotent or multipotent stem cells from adult tissue. Other types of cells including marrow-isolated adult multi-lineage inducible cells (MIAMI) [24] and single cell clones derived from bone marrow demonstrated the same multi-potential ability for differentiation. Unfortunately, the difficulty associated with obtaining, culturing, and expanding these pluripotent stem cells has proven to be a challenge.



In this study, we present our discovery of one group of novel cells isolated from human Bone Marrow (hBM). These cells, which we call SB cells, are less than 6 µm in diameter, express Lgr5, and experience significant increases in size and population after incubation in vitro. The addition of specific differentiation media at this stage caused the SB cells to differentiate into endoderm-, mesoderm-, and ectoderm-derived cell types. In vivo tracking of SB cells that were intravenously injected into the tails of sub-lethally irradiated SCID mice showed that the SB cells were able to develop into hepatocytes (endoderm), neurons (ectoderm), and skeletal muscle cells (mesoderm). Overall, these characteristics suggested that SB cells could play large roles in future stem cell-based therapeutic applications.



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