Special Issue on Stem Cells and Photobiomodulation Therapy

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Letter to the Editor
Photobiomodulation Therapy:
Communicating with Stem Cells for Regeneration?
Praveen R. Arany, DDS, PhD
To the Editor:
Never has there been a more exciting time in the human
race when the quest for knowledge has been expanded
outward to the farthest universe, as well as inward to suba-
tomic scales. It is likely not a mere coincidence that the ul-
timate frontier extending across all these vast scales happens
to be light—a still mysterious but omnipresent form of
physical energy whose impact on biological systems is still
being uncovered.
1
The use of photonics in medicine has al-
ready changed our healthcare system dramatically from
electronic access to data to better illumination fields, digital
cytology and pathology, endoscopy, and precision surgery
with lasers.
2
As in the clinical realm, biophotonics applica-
tions are leading research studies with innovations in optical
imaging, optogenetics, molecular analyses, as well as surgi-
cal and nonsurgical applications.
3
In other fields, the tremendous progress in our under-
standing of the human genome has paved the way for
precision-medicine initiatives to harness this information for
diagnoses and therapy.
4
Many of these breakthroughs have
been made possible by the use of induced pluripotent stem cell
technologies. These studies have demonstrated differentiated
(lineage committed) cells, either morphologically or func-
tionally, are in a stable but potentially reversible state.
5
There
have been major concerns on the promiscuity of the process of
lineage reversibility (epigenetic memory) and this remains an
area of intense investigation.
6
Nonetheless, the ability of a few
genes or small molecules to strikingly manipulate these stem-
like states has prompted exploration of clinical applicability
of these technologies for regenerative medicine.
A Biophysical Approach to Directing Differentiation:
A Question of Communication?
The major premise of directed differentiation is based on
the essential fact that every cell in our body is equipped with
the complete genetic information that is essentially fully
manipulatable. A stem cell or, a little less so, a progenitor cell
offers the most primed state in a cell’s potential for regen-
erative applications. It is, essentially, a blank permissive state
receptive to signals that could direct its behavior and func-
tions (Fig. 1). Regulatory cues such as small molecules
(drugs), biological (miRNA, shRNA, and transcription fac-
tors), or biophysical agents (light, ionizing radiation, ultra-
sound, and radiofrequency) would all be potential regulatory
modalities mediating biological communication. In this
context, the use of low dose biophotonics therapy termed
photobiomodulation (PBM) therapy, previously called low
level light/laser therapy, would represent such a biophysical
cell communication cue capable of modulating stem cell
behavior.
7
The PBM-induced biological changes could affect
stem cell bioenergetics, metabolism, signal transduction
pathways, epigenetic modulators, or gene expression to
evoke therapeutic benefits.
Sadly, since the inception of the PBM field, there has been
persistent skepticism on the biological efficacy of this treat-
ment modality. The inherent disbelief that such low doses
(approximating routine ambient light irradiant energy) can
evoke any substantive (nonthermal) biological response ap-
pears to be rather misplaced. It is indeed normal light irradi-
ances that enable vitamin-D metabolism in skin or modulate
the vision-enabling retinal pigment, rhodopsin.
8
It is also
prudent to point out that biological reactions are predomi-
nantly either biochemical or biophysical (conformational)
changes. Therefore, the use of PBM treatments not only offers
a reasonable biophysical modality to modulate biological
molecules therapeutically, but it may also be inherently har-
nessing naturally occurring photoreceptive biomolecules
playing key roles in physiological homeostasis processes.
Evidence for the Use of PBM Therapy with Stem Cells
The major purpose of this special issue is to provide a
collated overview of the progress and increasing excitement
for the use of PBM therapy with stem cells for regenerative
applications. The ethical controversies surrounding embry-
onic stem cells aside, a key fact remains that most tissues in
the adult human have a potent pool of resident stem and
progenitor cells. These cells play a pivotal role in routine
physiological turnover during tissue–organ maintenance as
well as contribute to repair after injury. This special issue
including comprehensive, state-of-the-art reviews as well as
primary research articles highlights the role of stem cells in
various niches that have been noted to be responsiveness to
PBM treatments. Three articles in this issue focus on fi-
broses in heart and kidney or damage to knee joint in animal
models, where PBM therapy in combination with stem cells
Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York.
Photomedicine and Laser Surgery
Volume 34, Number 11, 2016
ªMary Ann Liebert, Inc.
Pp. 497–499
DOI: 10.1089/pho.2016.4203
497

was noted to reduce damaged tissues and improve tissue
remodeling–regeneration. Interestingly, the three investiga-
tors take distinct approaches for the combinatorial treat-
ments. In the first study, O’Connor et al. injected exogenous
mesenchymal stem cells (MSCs) into circulation before
PBM treatment locally to the site of surgically induced renal
damage.
9
In the second study, Blatt et al. demonstrate mo-
bilization of bone marrow stem cells with PBM treatment
into circulation by treating long bones (tibia or iliac) directly
after cardiac injury.
10
In the third study, Fekrazad et al.
place scaffolds with seeded bone marrow-derived mesen-
chymal stem cells locally into osteochondral defects in
rabbit knee followed by PBM treatment.
11
All three studies
have noted the ability of PBM treatments to synergize with
the therapeutic benefits of stem cells in alleviating pain and
inflammation as well as promoting tissue healing in these
distinct ailments. Along with these primary research articles,
three reviews by Zhang and Liu (cardiac), Marques et al.
(dental), and Fekrazad et al. (MSCs) summarize prior
studies outlining the most effective PBM treatment param-
eters on these stem cells.
12–14
In other studies, investigators examined the effects of PBM
treatment on surgical wounds after bariatric surgery. Ojea
et al. noted decreased pain and inflammation along with re-
duced scarring in the PBM-treated surgical wounds.
15
In
another study, the mechanistic basis of improved skin or
mucosal wound healing was examined by assessing changes
in colony-forming units (CFUs) that is used as a functional
assay for epithelial stem cells.
16
Khan and Arany observed
that skin and mucosal keratinocytes have increased CFUs
after PBM treatment that would contribute to wound closure
(reepithelization). In another study, Myula and Abrahamse
note the paracrine interactions of stem cells and smooth
muscles in coculture models treated with PBM.
17
Besides
these highlighted studies, there is growing pieces of evidence
for the presence of stem cell niches at discrete anatomical
sites that appear to be amenable to PBM treatments such as in
the skeletal muscle and lung among many others.
18
Striking
clinical successes of PBM therapy in a wide range of disease
pathologies such as neuropsychology (e.g., traumatic brain
injury (Concussions), Alzheimer’s and Parkinson’s diseases,
multiple sclerosis, post-traumatic stress disorders, and de-
pression among others), ophthalmology (e.g., dry acute
macular degeneration and diabetic retinopathy), and derma-
tology (e.g., facial rejuvenation and hair growth) suggest that
there may be a common regenerative mechanism being har-
nessed, indicating putative roles for stem–progenitor cells at
these locations.
19,20
Clinical Delivery and Safety of PBM Therapy
with Stem Cells
The two major areas of PBM research have focused on
clinical validation and laboratory mechanisms. Although the
latter has focused on molecular pathways in biological
systems, the major advancement in clinical delivery has
emphasized standardizing and reporting PBM device pa-
rameters.
8
One study in this issue addresses one of the major
PBM delivery issues, which is the light beam profile. Ben-
edicenti et al. describe a flat top beam profile that enabled
uniform dose delivery to the treatment samples, noting
prominent changes in the mitochondrial electron transport
activity and cell metabolism. They summarize their findings
by suggesting that perhaps some of the discrepancies in
clinical outcomes with PBM are due to the Gaussian beam
profile of many current clinical biophotonics devices.
An interesting article in this issue attempts to address
effects of PBM treatments on cancer stem cells. There is
little evidence that nonionizing radiation wavelengths used
for PBM therapy have any appreciable potential for malig-
nant transformation. A recent article outlined the mecha-
nisms of near-infrared (NIR) laser phototoxicity and
FIG. 1. Outline of directed
differentiation strategies in re-
generative medicine. The upper
left image depicts a stem cell
amenable to extrinsic manipula-
tion by a range of regulatory cues
that result in reprogramming of
their genomes to initiate a differ-
entiated, morphological, and/or
functional state as shown in the
upper right image. The images in
the bottom represent the manipu-
latable, empty blackboard (black
slate) that can be programmed
with various regulatory (numbers,
alphabets, and symbols) cues that
communicate with the stem cell
to direct its differentiation to a
functional, differentiated state
(filled-in black slate).
498 ARANY

demonstrated the lack of any mutagenic or transformative
potential.
21
Nonetheless, there remain few concerns on how
the stimulatory effects of PBM noted in normal cells may
potentially influence pretransformed or cancer stem cells.
Crous and Abrahamse assess effects of dose-dependent
PBM treatments on lung cancer stem cells and speculate on
its clinical safety concerns.
22
Their technical assessment of
cell viability and proliferation deserves careful scrutiny and
could be interpreted contrarily. Nonetheless, this work raises
fascinating avenues to examine biological responses in
normal and malignant stem cell tissues, especially the nature
of cellular (epigenetic) memory, to PBM treatments.
In summary, this special issue on PBM therapy and stem
cells attempts to present some of the recent exciting progress
in this area. The field of regenerative medicine appears to be
poised at practically harnessing the tremendous advances we
have made with stem, cell-molecular, and developmental
biology. Indeed, the premise of directing differentiation
appears to present the next formidable challenge in clinical
translation of stem cell biology to regenerative medicine.
Besides conventional pharmaceutical, biological, and bio-
material approaches maintain center stage in these attempts,
biophysical modalities such as PBM therapy could add an
additional approach to the clinical translational regenerative
armamentarium.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Praveen R. Arany
3435 Main Street
B36A Foster Hall
Department of Oral Biology
School of Dental Medicine
University at Buffalo
Buffalo, NY 14214
E-mail: prarany@buffalo.edu
Received: August 4, 2016.
Accepted after revision: August 5, 2016.
Published online: October 31, 2016.
LETTER TO THE EDITOR 499