Ankrum, James A

Kokabu, Shoichiro

Liu, Renjing

Lowery, Jonathan W, Ph.D.

English

Marian University Indianapolis

MUShare
Scholarship, History, Art, Research, and Engagement
Faculty Publications and Research College of Osteopathic Medicine
2016
Targeted Strategies to Modulate Stem-Cell-
Relevant Pathways.
Jonathan W. Lowery Ph.D.
Marian University - Indianapolis, jlowery@marian.edu
James A. Ankrum
University of Iowa
Shoichiro Kokabu
Saitama Medical School
Renjing Liu
University of Sydney, Australia
Follow this and additional works at: http://mushare.marian.edu/com_fp
Part of the Medicine and Health Sciences Commons
This Article is brought to you for free and open access by the College of Osteopathic Medicine at MUShare. It has been accepted for inclusion in
Faculty Publications and Research by an authorized administrator of MUShare. For more information, please contact emandity@marian.edu.
Recommended Citation
Lowery JW, Ankrum JA, Kokabu S, Liu R. “Targeted Strategies to Modulate Stem-Cell-Relevant Pathways.” Stem Cells International.
2016:1859456. PMC5040791. PMID: 27703484.
Editorial
Targeted Strategies to Modulate Stem-Cell-Relevant Pathways
Jonathan W. Lowery,1 James A. Ankrum,2,3 Shoichiro Kokabu,4,5 and Renjing Liu6,7
1Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN, USA
2Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA
3Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
4Division of Molecular Signaling and Biochemistry, Department of Health Improvement, Kyushu Dental University, 2-6-1 Manazuru,
Kokurakita-ku, Kitakyusyushi, Fukuoka 803-8580, Japan
5Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-machi,
Iruma-gun, Saitama 350-0495, Japan
6Agnes Ginges Laboratory for Diseases of the Aorta, Centenary Institute, Camperdown, NSW, Australia
7Sydney Medical School, University of Sydney, Sydney, NSW, Australia
Correspondence should be addressed to Jonathan W. Lowery; jlowery@marian.edu
Received 9 August 2016; Accepted 9 August 2016
Copyright © 2016 Jonathan W. Lowery et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Modulation of stem cell behavior is of significant interest to
the biomedical community and could lead to novel therapeu-
tic advances in treating disease. Achieving this goal requires
specific strategies that manipulate the pathways regulating
stem cell plasticity and behavior. The accumulating evidence
indicates that just a few main signaling pathways regulate
most types of stem cells, which suggests that strategies that
modulate one type of stem cell might hold broad usefulness.
However, as stem cell research becomes more and more
specialized, investigators studying a particular pathway or
behavior in one specialty can miss a breakthrough advance-
ment made in another specialty.
In this special issue we have collected reports and reviews
of pathways that are critical to regulating the function and fate
ofmesenchymal stem cells (MSCs), induced pluripotent stem
cells (IPSCs), and endothelial progenitor cells (EPCs). While
each report is focused on the fate and function of a particular
type of progenitor cell or a particular pathway, mechanisms
at play in one cell type may be directly relevant to other cell
types as well.
The multipotent nature of MSCs makes them an attrac-
tive cellular source for regenerative medicine. While many
reports exist describing the potential of MSC to repair dam-
aged tissues following trauma, our understanding of the role
of MSC in repair of polytrauma, that is, in tissues suffering
more than two injuries, is still in its infancy. In this special
issue, M. Huber-Lang and colleagues provided a summary of
studies that shed light on the potential of MSC as a therapeu-
tic target for treatment of polytrauma. Moreover, the authors
present examples that add to both sides of the debate on
whether MSC are “actors” that drive tissue regeneration or
are “targets” for attacks by the immune system following
polytrauma.
S. Kokabu et al. also focus on MSCs, examining the
reciprocal relationship between differentiation of this cell
type into osteogenic versus adipogenic lineages. Particular
attention is paid to the function of the transcriptional reg-
ulator Transducin-Like Enhancer of Split 3 (TLE3), which
has recently been implicated in regulating the commitment
between these two lineages. Additionally, S. Kokabu and col-
leagues propose future areas of researchwhichmay lead to the
ability to control adipogenic versus osteogenic differentiation
in the bone marrow microenvironment.
Related to this, J. W. Lowery et al. survey the strategies
that are available to modulate the Bone Morphogenetic
Protein (BMP) signaling pathway, which potently induces
both osteogenic and adipogenic differentiation of MSCs.The
authors detail the currently available natural and engineered
ligands, extracellular antagonists, ligand traps, and kinase
inhibitors. Numerous examples of each strategy in specific
Hindawi Publishing Corporation
Stem Cells International
Volume 2016, Article ID 1859456, 2 pages
http://dx.doi.org/10.1155/2016/1859456
2 Stem Cells International
settings and applications are presented. J. W. Lowery and
colleagues also propose future areas for study in order to
advance the ability to control behavior of MSCs, other stem
cell populations, and somatic cells alike.
J. Zhao et al. examine the ability of late-outgrowth EPCs
(LO-EPCs) to home to sites of injury after intravenous infu-
sion via a series of in vitro experiments. LO-EPCs are capable
of differentiating into endothelial cells, but are a rare cell
type in circulation, making their ex vivo expansion necessary
prior to therapy. In contrast to leukocytes and MSC which
exhibit enhanced adhesion to inflamed endothelium, J. Zhao
and colleagues reported no enhancement in LO-EPC adhe-
sion in inflamed in vitro conditions. However, attachment
was enhanced when the subcellular extracellular matrix
was exposed. Disruption of endothelial barrier integrity by
subconfluent seeding or incubation with anti-VE cadherin
blocking antibodies resulted in increased LO-EPC adhesion,
which the authors go on to show that it appears to be
dominated by adhesion to fibronectin and vitronectin in the
ECM. Thus, in contrast to MSC and leukocytes, disruption
of endothelial integrity appears to be critical to facilitate LO-
EPC homing.
Finally, P. Nagaria et al. examine how the method of
conferring pluripotency affects the DNA damage response in
cord blood myeloid progenitors and fibroblasts. The authors
find that, in contrast to standard methods, a high-fidelity
stromal-activatedmethod results in IPSCs that closely resem-
ble embryonic stem cells in their ability to repair double-
stand DNA damage via non-homologous end joining and
in their expression of c-MYC-mediated transcriptional sig-
nature. These findings are highly relevant to investigators
working in the IPSC field and are potentially applicable to the
safe clinical translation of IPSC-based therapies in patients.
Jonathan W. Lowery
James A. Ankrum
Shoichiro Kokabu
Renjing Liu
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Targeted Strategies to Modulate Stem-Cell-Relevant Pathways.

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Targeted Strategies to Modulate Stem-Cell-Relevant Pathways.

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