Med Lasers 2020; 9(2): 134-141
Effects of Photobiomodulation on Stem Cells Important for Regenerative Medicine
So-Young Chang1, Nathaniel T. Carpena2, Bong Jin Kang3, Min Young Lee1,2
1Beckman Laser Institute Korea, Dankook University, Cheonan, Korea
2Department of Otolaryngology-Head & Neck Surgery, College of Medicine, Dankook University, Cheonan, Korea
3Department of Anesthesia and Pain medicine, College of Medicine, Dankook University, Cheonan, Korea
Correspondence to: Min Young Lee
Department of Otolaryngology-Head & Neck Surgery, College of Medicine, Dankook University, 119 Dandae-ro, Cheonan 31116, Korea Tel.: +82-41-550-1785
Fax: +82-41-559-7838
Received: August 4, 2020; Accepted: October 5, 2020; Published online: December 31, 2020.
© Korean Society for Laser Medicine and Surgery. All rights reserved.

The use of stem cell therapy to treat various diseases has become a promising approach. The ability of stem cells to self-renew and differentiate can contribute significantly to the success of regenerative medical treatments. In line with these expectations, there is a great need for an efficient research methodology to differentiate stem cells into their specific targets. Photobiomodulation (PBM), formerly known as low-level laser therapy (LLLT), is a relatively non-invasive technique that has a therapeutic effect on damaged tissue or cells. Recent advances in adapting PBM to stem cell therapy showed that stem cells and progenitor cells respond favorably to light. PBM stimulates different types of stem cells to enhance their migration, proliferation, and differentiation in vitro and in vivo. This review summarizes the effects of PBM on targeted differentiation across multiple stem cell lineages. The analytical expertise gained can help better understand the current state and the latest findings in PBM and stem cell therapy.
Keywords: Stem cell differentiation; Photobiomodulation; Low-level laser therapy; Regenerative application; Therapeutic effect

Stem cells play an important role as the source of tissue-organ maintenance as they pitch in for repair of injured tissues with their self-renewing capacity and ability to differentiate into multiple target phenotypes. Therefore, stem cell therapy may be a promising treatment option for the regenerative medicine field. 1

There are two types of stem cells: embryonic stem cells (ESC) and adult stem cells. However recently, stem cell research has been conducted primarily using adult stem cells. Between 2013 up until writing this review, only one published study used ESC in relation to PBM research, 2 while all other research papers were using adult stem cells. Adult stem cells exist in various organs of our body and are capable of regenerating when the body is damaged. Mesenchymal stem cells (MSC) can be easily isolated from adipose, bone marrow, umbilical cord, and dental pulp, have been studied extensively in tissue engineering and regenerative medicine of different organs as an alternative to conventional treatment methods. 3-7 Despite the high differentiation potential, the slow proliferation rate of MSCs is an important factor inhibiting its development as an effective treatment. Therefore, establishing a way to accelerate the MSC’s proliferation process is a very important requirement for its success.

Photobiomodulation (PBM) is a non-thermal and non-invasive stimulating process to target using wavelengths from the red to near-infrared light spectrum (600 to 1000 nm). Formerly called as low-level laser (light) therapy (LLLT), it has been reported that both coherent and non-coherent light sources such as light-emitting diodes (LEDs) have the same therapeutic effect. In light of this, the associations have agreed and acknowledged the renaming of LLLT into PBM. 8 Its beneficial effects have been shown in many different diseases by modulating cellular functions such as differentiation, proliferation and migration leading to tissue or cell regeneration. In recent years, the potential importance of PBM is emerging as a clinical tool in regenerative medicine. 9-11 PBM has been reported to have positive and promising effects in relation to MSCs proliferation and differentiation. 6,12-17 However, the bio-stimulation mechanisms of these effects remain partially unclear.

In this review, we summarized the parameters and effects of PBM when applied to various stem cell proliferation and target differentiation in in vitro and in vivo papers published between 2013-2020 for to understand the current state and latest results of PBM in stem cell research.


Effect of PBM on human adipose derived stem cells (hADSCs)

MSCs are capable of differentiation into multiple lineages such as osteogenic, adipogenic and chondrogenic cell lines. Among the MSCs, ADSCs could be choosen due to their ease of isolation. In vitro and in vivo studies have shown that PBM can induce ADSC to differentiate into multiple mature cell phenotypes including adipocytes, osteoblasts and chondrocytes. Recently, research has focused to determine whether PBM has the ability of encourage ADSC to differentiate in order to use for regenerative medicine. When analyzing the wavelength of PBM involved in the proliferation and differentiation of ADSC, light source parameters used red light red light from 630 to 660 nm wavelengths as well as near-infrared lights from 809, 810 and 980 nm wavelength bands. Although studies have also been conducted on muscle 18 and bone formation, 15,19 most of them are experiments aimed at regenerating wound tissues. 5,13,14,18,20-25 The equipment types, wavelengths and energy densities used in the experiments are summarized in Table 1.

Table 1 . Human adipose stem cells related to photobiomodulation (PBM) application

Type of light deviceWavelength (nm)Energy density (J/cm2)Related research fieldsCriteriaRef.
InGaAIP laser66020, 70, 180In vitroProliferation at 20 and 70 J/cm25
NIR laser8900.2, 6 days per week for 16 daysIn vivo, DM woundAnti-inflammatory, angiogenetic differentiation on day 16.13
Red and NIR diode laser635 and 8090.5, 1, and 2In vitro, osteogenesisOsteogenic differentiation in the unproliferation state14
LED, filtered lamp, red diode laser and NIR diode laser415, 540, 660, and 8103In vitro, osteogenesisProliferation at 660 and 810 nm15
Red diode laser6365In vitro, smooth muscle cellsSmooth muscle cells diffentiation18
LED, filtered lamp, red diode laser and NIR diode laser420, 540, 660, and 8103, five timesIn vitro, osteoblastsProliferation and osteogenic differentiation at 420 and 540 nm19
Red diode laser66011-16In vitro, woundProliferation20
Red diode laser635 and 6554In vitro, woundProliferation and migration21
LED6606In vivo, angiogenesis skin flap ischemiaFunctional endothelial differentiation22
NIR light810 and 9800.03, 0.3, 3, and 20In vitroProliferation differentiation in 980 nm23
He-Ne and diode laser632.8, 630, and 8100.6, 1.2, and 2.4In vitro, woundProliferation more effective in hASC24
Red laser66070, three times a week, total 10 timesIn vivo, wound Proliferation increase collagen birefringence25

InGaAIP, indium-gallium-aluminum phosphide diode laser; NIR, near infrared; DM, diabetes mellitus; LED, light-emitting diode; He-Ne, helium‑neon; hASC, human adipose stem cell.

Effect of PBM on human dental pulp stem cells (hDPSCs)

DPSCs are another representative of MSCs, which are easily isolated from the teeth without an invasive treatment. In addition, DPSCs are a promising source of cells for various regenerative medicine applications especially for dental tissue engineering. DPSCs are derived from the neural cap of the tooth, therefore are distinguished from bone marrow MSCs due to their different developmental origin. These property are being utilized for neurological and odontogenic differentiation. Based on the studies that confirm the effectiveness of PBM on DPSCs, 7 studies used red laser (660 nm), 7,16,26-30 and the two other articles conducted their studies using near-infrared wavelengths (808 and 810 nm). 12,31 They confirmed that the application of PBM with the red wavelength is very effective for the proliferation and differentiation of DPSC. The equipment types, wavelengths and energy densities used in the experiment are summarized in Table 2.

Table 2 . Human dental pulp stem cells related to PBM application

Type of light deviceWavelength (nm)Energy density (J/cm2)Related research fieldsCriteriaRef.
InGaAlP laser6601, 3, 5, 10, 15, or 20In vitro, osteogenesisProliferation in the undifferentiated state7
CW and PW-LED8100.038In vitroCW-PBM; proliferation PW-PBM; differentiation12
GaAlAs diode laser6602 and 4, every 3 days for 4 weeksIn vitro, osteogenesisOdontogenic differentiation with Mg-based scaffolds16
CW GaAlAs diode laser6600.14In vitro, osteogenesisImprove osteogenic differentiation26
InGaAlP laser6603 and 5In vitro, cell sheetsFunctional differentiation of cells (collagen and fibronectin)27
InGaAlP diode laser66033.33In vitro, woundProliferation and migration28
Fiber optic diode laser66055.2, 22.1, 1.6, and 0.6In vitro, neurodegenerative disorderDopaminergic neuronal differentiation29
InGaAlP6603 and 5In vitro/in vivoProliferation differentiation30
GaAlAs laser 80830 mWIn vitro, neuronProliferation neurogenesis differentiation31

CW, continuous wave; PW, pulse wave.

Effect of PBM on human bone marrow stem cells (hBMSCs)

MSCs can also be isolated from human bone marrows and utilized for therapeutic purposes. BMSCs are able to support angiogenesis and enhance the formation of new microvessels, secrete nerve growth factors and restore nerve function after ischemic stroke, as well as used to treat non-healing fractures. 32 The research results of BMSC and PBM are widely applied to wound healing, fat production and bone formation. Studies were done with the combination of PBM and BMSCs using visible wavelength was also applied. 17,33 However, more significant results came from the use of wavelengths in the near infrared region (808, 890, 905 and 1064 nm), which showed remarkable results in wound healing and bone formation. 32,34-38 The equipment types, wavelengths and energy densities used in the experiment are summarized in Table 3.

Table 3 . Human bone marrow stem cells related to PBM application

Type of light deviceWavelength (nm)Energy density (J/cm2)Related research fieldsCriteriaRef.
Red diode laser630 and 6601In vitro, osteogenesisOsteogenic differentiation17
NIR laser808 and 9050.93-6.27In vitro, woundProliferation32
LED, diode laser and NIR diode laser405, 635, and 8080.4In vitro, boneProliferation, osteogenic differentiation at 635 nm 33
NIR laser8900.2In vivo, DM wound healingProliferation shortened the inflammatory phase34
NIR laser8900.2, 6 days a week for 15 daysIn vivo, DM woundInduced anti‐inflammatory and angiogenic activities35
NIR diode laser8080.5, 1, 2, 3, and 4In vitro, in vivo, gingival woundGingival migration at 1 J/cm2 in unproliferation36
Collimated laser to IR light10648.8, 17.6, and 26.4In vitro, adipocyteAdipogenic differentiation37
InGaAlP red laser6602.5, 5.0, and 7.5In vitro, osteogenesisOsteogenetic proliferation38

IR, infrared.

Effect of PBM on human umbilical cord blood-derived MSCs (hUCMSCs)

In the research of UCMSC and PBM, studies using animal-derived mesenchymal stem cells isolated from human umbilical cord blood have also been reported. UCMSCs also showed the ability of self-renewal and capacityto differentiate into multiple lineages. Compared to the ethical hurdles faced by the use of ESCs, the use of hUCMSCs for scientific studies is regarded as ethically acceptable. However, the combination of UCMSC and PBM with the red wavelength (620, 625, 633, and 635 nm) was effective for the induction of blood vessel and bone formations. 4,6,39,40 The equipment types, wavelengths and energy densities used in the experiments are summarized in Table 4.

Table 4 . Human umbilical cord blood-derived mesenchymal stem cells (MSCs) related to PBM application

Type of light deviceWavelength (nm)Energy density (J/cm2)Related research fieldsCriteriaRef.
LED array6330.3, 1, 3, and 6Angiogenesis Radiation-induced enteropathyProliferation4
Red and NIR Laser635 and 8080 to 10In vitroNeural differentiation 808 more effective6
LED6202In vitro, osteogenesisProliferation and osteogenic differentiation39
LED6251.9In vitro, gametogenesisProliferation and differentiation40

Effect of PBM on animal derived mesenchymal stem cells

Cases of PBM application on animal-derived mesenchymal stem cells have also been reported. The animals used in the experiments were mouse, 41 rabbit, 42-44 rat 45-53 and equine. 54 Similar to human-derived MSCs, the wavelengths used for PBM on animal cells were in the visible region of the spectrum (blue, green, and red) 43,44,46,48-50,52 to near-infrared region (808-1064 nm).41,42, 45,47,51,53,54 The effects showed a positive effect on wound healing, bone regeneration, and nerve regeneration. The equipment types, wavelengths and energy densities used in the experiments are summarized in Table 5.

Table 5 . Animal derived MSCs related to PBM application

Type of light deviceWavelength (nm)Energy density (J/cm2)Related research fieldsCriteriaRef.
Mouse BMSCDiode laser80864, every 24 h for 0, 5, 10, and 15 daysIn vitro, osteogenesisOsteoblast differentiation under down-regulation of the pro-inflammatory cytokines 41
Rabbit BMSCsGaAlAs laser8104, every other day for 3 weeksIn vivo, woundPromote the healing of osteochondral defects compared with the use of BMSCs alone42
Rabbit BMSCsBlue, green, red, and IR laser470, 532, 660, and 8104, every other day for 3 weeksIn vitro, osteogenesisProliferation and differentiation in red and IR lasers and green43
Rabbit BMSCsLaser485, 532, 660, and 8104, for 3 weeksIn vitro, chondro-genesisOsteogenesis (660 and 810) Cartilage differentiation (810 and 810+532)44
ADSCNIR laser8902.196 and 40.824In vivo, woundProliferation45
Rat ADSCGaAlAs laser66010, 18, and 27In vitroProliferation inhibited oxidative stress 46
Rat ADSCsNIR light80871.2In vivodownregulation of pro-inflammatory cytokines and MPs47
Rat BMMSCHe-Ne laser632.81.2In vivoProliferation e osteogenic differentiation48
Rat BMMSCsHe-Ne laser +alendronate632.81.2In vitroProliferation osteogenic differentiation49
Rat BMMSCsHe-Ne laser632.81.2, three times on other daysIn vivo, osteogenesisProliferation and differentiation 50
Rat BMMSCsNIR laser8901.5, three times per week for 8 weeksIn vivo, osteoporosisProliferation51
Rat BM-MSCsHe-Ne laser632.80.5, 1, and 2, every other day for three timesIn vitro, in vivo, diabetic Proliferation at 1 J/cm2 under anti-apoptosis52
Rat BMSCsPW IR laser8901.5, for 3 times a weekIn vitro, neuronProliferation neural differentiation53
Equine- MSCNd:YAG laser10649.77In vitro, angiogenesisNo difference in viability but increased of IL-10 and VEGF54

BMSC, bone marrow mesenchymal stem cells; ADSC, adipose-derived stem cells; Nd:YAG, neodymium-doped yttrium aluminum garnet; VEGF, vascular endothelial growth factor.

Potential PBM mechanism for stem cell proliferation and differentiation

These reviewed papers suggest several mechanisms in which PBM affects stem cell proliferation and differentiation. What is commonly suggested as a mechanism of PBM is that it causes anti-apoptosis by increasing ATP and reducing oxidative stress. 30,53 PBM influences ADSCs in wound healing through anti-apoptosis regulation (upregulated Bcl-2 and downregulated Bax), migration via ERK1/2 and FAK pathway, and inhibited the downregulated TGF-β1 and Notch-1 expression. 20 Another published skin flap ischemia study suggested the possibility of PBM effect was mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathway. 22 Other mechanisms showed a shortened inflammatory stage in diabetic wound model by increasing the gene expression of bFGF, SDF-1 α, and HIF-1α which results in the wound healing acceleration. 34 It has also been reported that PBM enhances MSC migration through the ROS/JNK/NF-κB/MMP-1 pathway, which increases protein expression of p-JNK, p-IκB, p65 and MMP-1. 36

Until now, the parameters of PBM for prevention and treatment of the diseases have not been fully established. The irradiation dosage is one of the important parameters to induce PBM efficiently to stem cells as well as other cell types. PBM is known to have a bipolar effect, as for instance, by stimulating TGF with low-dose or suppressing TGF with a relatively high-dose of LED irradiation for improving skin rejuvenation or treating skin fibrosis. 55,56 Therefore, it is necessary to accumulate data on dose-dependent effects of PBM. The results of this experiment will help us understand and utilize PBM for stem cell research.


The application of PBM can be a promising combination to improve mesenchymal stem cell therapy (Fig. 1). Well defined parameters, such as wavelength range, irradia-tion time, and energy density, can enhance proliferation or differentiation of stem cells.

Figure 1. Schematic representation of the application of photobiomodula­tion (PBM) on stem cell and thera­peutic benefits. PBM using wave­lengths from the red to near-infrared light spectrum (600 to 1000 nm) induces mesenchymal stem cell proliferation and differentiation for tissue engineering and regenerative medicine. hASC, human adipose stem cell; hUCMSCs, human umbilical cord blood-derived MSCs; hDPSC, human dental pulp stem cell; hBMMSCs, human bone mar­row mesenchymal stem cells.

However, in order to translate into a reliable clinical application, it is necessary to provide a more detailed sci-entific evidence supporting the clinical use of stem cells by establishing a clear mechanism of how PBM interacts with various stem cells to achieve the intended medical innovations.


This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2020R1C1C1009695).

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