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The application of extracorporeal shock wave therapy on stem cells therapy to treat various diseases

Stem Cell Research & Therapy volume 15, Article number: 271 (2024) Cite this article

Abstract

In the last ten years, stem cell (SC) therapy has been extensively used to treat a range of conditions such as degenerative illnesses, ischemia-related organ dysfunction, diabetes, and neurological disorders. However, the clinical application of these therapies is limited due to the poor survival and differentiation potential of stem cells (SCs). Extracorporeal shock wave therapy (ESWT), as a non-invasive therapy, has shown great application potential in enhancing the proliferation, differentiation, migration, and recruitment of stem cells, offering new possibilities for utilizing ESWT in conjunction with stem cells for the treatment of different systemic conditions. The review provides a detailed overview of the advances in using ESWT with SCs to treat musculoskeletal, cardiovascular, genitourinary, and nervous system conditions, suggesting that ESWT is a promising strategy for enhancing the efficacy of SC therapy for various diseases.

Introduction

Stem cells, also known as SCs, are undifferentiated cells found in embryos, fetuses, and adults, giving rise to specialized cells that make up tissues and organs, and possessing the ability to renew themselves and differentiate into various cell types [1]. Specifically, Mesenchymal Stem Cells (MSCs), which are a type of versatile stem cells, have the ability to transform into various types of cells [2], including nerve cells, bone cells, hepatic cells and vascular endothelial cells [3,4,5,6]. MSCs are multipotent cells found in various human tissues, known for their unique biological properties including low immunogenicity, potent immunomodulatory and immunosuppressive capabilities, particularly homing ability [7]. In the process of homing, MSCs migrate to the site of injury to exert therapeutic effects primarily through paracrine mechanisms [8], releasing a diverse array of functional molecules such as growth factors, inflammatory factors, chemokines, and extracellular matrix (ECM) components [9] to promote nerve repairment, bone healing, liver repairment and revascularization. The preconditioning strategy can improve the humming of homing of MSCs. For instance, ESWT has been shown to enhance the homing of MSCs in vivo [10].

Although stem cell-based therapies hold promise for treatment, there are various technical obstacles to overcome, such as the poor retention and survival of stem cells in the damaged area post-transplantation, and the restricted effectiveness of neural differentiation. These bottlenecks ultimately restrict the therapeutic effects of SC treatments [11]. Hence, a new and effective approach is necessary to enhance the therapeutic effects of stem cell, especially MSCs. (Fig. 1)

Fig. 1
figure 1

SCs are featured by self-renewal capacity and multi-lineage differentiation potential. In particular, MSCs, as a type of multipotential stem cells, can differentiate into multipotential cells, including nerve cells, bone cells, hepatic cells and vascular endothelial cells. Stem cells are essential in regenerative medicine, serving as a source of cell regeneration and releasing paracrine factors to promote nerve repairment, bone healing, liver repairment and revascularization. (by figure draw)

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Several preconditioning strategies have been used to improve the therapeutic effect of SCs on various diseases, including hypoxia, gene modification, culture environment improvement, thermosensitive hydrogel, and so on [12]. However, the above mentioned strategies have their own limitations, for instance, low efficiency, complex operation process, etc. A promising preconditioning strategy, which can not only promote the survival, paracrine and migration ability of SCs but also do not exert harmful effects, can be deemed as the most appropriate preconditioning method to treat various diseases. For intance, Extracorporeal shock wave therapy (ESWT) is a non-invasive, high-efficient and easy to operate therapeutic method.

Shock waves (SWs), ranging in frequency from 16 Hz to 20 MHz, are characterized by a brief period of intense positive amplitude followed by a prolonged period of low negative amplitude. This unique waveform allows for the delivery of energy to distant targets while minimizing the impact on surrounding tissue. Moreover, SWs, divided into concentrated and divergent types, exhibit characteristics such as elevated peak pressure (exceeding 100 MPa), rapid pressure increase (less than 10 ns), and brief duration (less than 10µs) [13].

ESWT is a non-invasive treatment form of physical therapy that applies tension and compression to tissue cells by passing through various mediums, which originates from extracorporeal shock wave lithotripsy (ESWL) [14]. ESWT systems can be categorized into three types based on their sound sources, including electro-hydraulic system, electromagnetic system, and piezoelectric system [15]. Various factors, such as air pressure, energy flux density (EFD) in mJ/mm2, pulse count, and frequency in Hz, can impact the efficacy of ESWT. EFD is a measure of the energy intensity of shock waves in a specific location [16] and is used to classify ESWT into low, medium, and high energy levels depending on the EFD value. Additionally, the validity of ESWT is influenced by the depth of penetration [16]. Generally, focused ESWT (fESWT) can reach tissues up to a depth of 12 cm, while radial ESWT (rESWT) has a penetration depth of only 3–4 cm. The treatment site of ESWT can be determined through palpation, ultrasound, or x-rays [17]. Depending on the treatment area, patients may be positioned in prone, side lying, or sitting postures, and the intensity is adjusted according to the responses of patients [18].

When cells experience mechanical shock, they convert these mechanical signals into biogenic signals. This process triggers anti-inflammation, angiogenesis, immunomodulatory, cell proliferation and cartilage protection [19]. ESWT can trigger the extracellular matrix and cytoskeleton by stretching channels, serving as a mechanical force source [20]. The initiation of this process stimulates the proliferation, migration, and differentiation of stem cells, which are essential for the healing and regeneration of tissues [21]. ESWT has become increasingly popular as a treatment choice for a range of musculoskeletal conditions [22], including plantar fasciitis, tennis elbow [23], and nonunion [24], due to its positive impacts.

Following injury, mesenchymal stem cells demonstrate mobilization and subsequent homing to the site of injury [25]. These cells possess potent immunomodulatory and regenerative capabilities, positioning them as a promising therapeutic avenue for various clinical conditions [26]. ESWT has been demonstrated to enhance the migration and recruitment of a significant quantity of mesenchymal stem cells to the targeted regions [27]. Additionally, ESWT has been utilized in the treatment of wounds [28, 29] and urinary tract diseases [30, 31]. In summary, as is shown in Fig. 2, the applications of ESWT on SC therapy are mainly focusing on the musculoskeletal, cardiovascular, genitourinary, and nervous system conditions.

Fig. 2
figure 2

ESWT is a physical stimulation that applies tensile and compressive stress to tissue cells, converting mechanical signals into biogenic ones. This process triggers healing mechanisms such as anti-inflammation, angiogenesis, and stem cell activation. ESWT can promote the proliferation, differentiation, migration and recruitment of SCs, which can improve the effect of SC therapy for various diseases, including musculoskeletal system diseases, cardiovascular system diseases, genitourinary system diseases and nerve system diseases. (by figure draw)

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The mechanical stimulation of shock waves from ESWT can potentially influence the biological functions of stem cells, such as proliferation, migration, recruitment, and differentiation [32, 33].

First, the proliferation of cells is essential for the regeneration of tissues, and ESWT can enhance the proliferation of different kinds of stem cells, including bone marrow stem cells (BMSCs), adipose-derived stem cells (ADSCs), endothelial progenitor cells (EPCs), and neural stem cells (NSCs) [34, 35]. For example, ESWT enhances the proliferation of BMSCs and ADSCs in vitro, possibly involving the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3 kinase/protein kinase B (PI3-K/Akt) pathway, and nuclear factor kappa B (NF-kB) signaling pathway [36, 37]. ESWT led to an elevation in the levels of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), subsequently promoting the proliferation of EPCs in individuals with coronary artery disease (CAD) [38]. In vitro studies have shown that ESWT can boost the proliferation of NSCs by activating the PI3K/Akt, Wnt/β-catenin, and Notch pathways [39]. Furthermore, the mechano-transduction signaling axis of mTOR- focal adhesion kinase (FAK) is activated by ESWT, leading to increased proliferation of MSCs in vitro [40].

Second, ESWT has also been shown to facilitate the migration and recruitment of numerous MSCs to affected area [27]. In vivo migration assays conducted by Xu et al. demonstrated that ESWT may promote the migration of ADSCs by upregulating the CXC chemokine ligand 5 /CXC chemokine receptor 2 (CXCL5/CXCR2) axis. Similarly, in a rat model of bladder dysfunction, ADSCs that underwent ESWT showed enhanced migration abilities to the damaged bladder in comparison to ADSCs that did not receive treatment [37]. Moreover, ESWT can directly or indirectly promote the production of transforming growth factor β1 (TGF-β1) and VEGF-A in wound tissue in a rat model with a segmental femoral defect, leading to the recruitment of MSCs [33].

Third, ESWT has been demonstrated to enhance the differentiation of different categories of stem cells, such as ADSCs, BMSCs, and NSCs. Schuh et al. demonstrated that ESWT increased the differentiation of human ADSCs into adipogenic, osteogenic, and Schwann-like cells at an energy level of 0.09 mJ/mm2 in cell experiments [41]. ESWT can enhance the growth and differentiation of BMSCs into osteoprogenitor cells in a rat model by potentially increasing transforming growth factor beta-1 (TGF-β1) levels [34]. Moreover, ESWT promoted the differentiation of NSCs through the Wnt/β-catenin pathway, leading to the improvement of neurological function in rats after experiencing cerebral ischemia [42]. To sum up, ESWT can significantly promote the biological activities of stem cells, such as proliferation, differentiation, migration and recruitment. (Fig. 3).

Fig. 3
figure 3

ESWT can positively influence the biological effects of stem cells, including proliferation, differentiation, migration and recruitment, through various signaling pathways, for instance, MAPK, PI3K/Akt, NF-kB, et al. (by figure draw)

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Application of ESWT on stem cells therapy for musculoskeletal system diseases

Osteoarthritis

Osteoarthritis (OA) is the most common degenerative arthrosis and the leading cause of pain and disorders in the elderly [43]. It is characterized by the destruction of articular cartilage and remodeling of other joint tissues [44]. However, the regenerative ability of articular cartilage is extremely limited due to its non-vascular nature [45, 46]. To address this, a variety of therapies have been used to promote regeneration cartilage tissue regeneration [47, 48]. Due to the limited renewal capacity and matrix generation of chondrocytes after cell expansion, stem cells have emerged as a rational method for promoting cartilage regeneration [49, 50]. Specifically, BMSCs, ADSCs [51], and subchondral bone stem/progenitor cells (SCB-SPCs) [52] are potential options for repairing cartilage tissue. However, they do have several limitations, for instance low proliferative potential, loss of stemness, and the potential for artifactual chromosomal changes [53,54,55]. Therefore, novel methods to improve the effect of SCs for treating diseases are urgently required.

ESWT has been shown to enhance the therapeutic potential of stem cells [56]. First, ESWT has been shown to enhance cell proliferation and self-renewal in a rabbit study, potentially boosting MSC proliferation by aiding in the transition from the G1 to the S stage of the cell cycle and enhancing the capability of MSCs to repair cartilage impairment [56]. Second, in a rat model of knee osteoarthritis, the combination of ADSCs and ESWT decreases the inflammation-induced levels of TNFα-stimulated gene-6 (TSG-6), proteoglycan-4 (PRG-4), bone morphogenic protein-2 (BMP-2), and bone morphogenetic protein-6 (BMP-6), and enhances the levels of type II collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1), a modulator of matrix metalloproteinase. Thus, the combination of ESWT and ADSCs can inhibit synovitis and improve the damage of Chondral and osteochondral [57]. Additionally, ESWT is able to alleviate the symptoms in OA rats, inhibit cartilage degeneration, and accelerate the repairment of subchondral bone by triggering the Wnt5a/Ca2 + signaling pathway in BMSCs [58]. Furthermore, in a model of osteochondral injury, ESWT could potentially enhance the regeneration of SCB-SPCs by activating yes-associated protein (YAP) in vitro and promote the capabilities of SCB-SPCs in vivo [59]. Therefore, utilizing shock waves for modulating stem cell behavior represents a promising approach in facilitating cartilage repair.

Bone defects

Bone defects can result from skeletal diseases, congenital defects, trauma, and tumor excisions which require bone repair [60,61,62,63]. The major approaches for repairing bone defects are autografts and allografts. However, the application of autografts is limited due to harvest limitations and donor site injuries [64]. Immunogenic responses from host tissues when using allografts can hinder osteogenesis [65]. To tackle these challenges, advanced tissue engineering techniques have been employed [66]. As one of the tissue engineering methods, stem cell treatment has been used widely in bone tissue engineering. Nevertheless, there are still some unsolved problems. For instance, the apoptosis of transplanted cells limits tissue repair [67]. Consequently, alternative interventions are urgently required to boost the therapeutic effect of stem cells.

Preconditioning with ESWT may be a valuable method to improve the therapeutic potential of MSCs [68]. ESWT enhances the growth of mesenchymal cells and their differentiation into bone-forming cells by upregulating BMP expression in rats with a segmental femoral defect, leading to increased formation of new bone [69]. Moreover, TGF-β1 takes part in the recruitment and differentiation of MSCs, and ESWT can directly or indirectly promote the expression of TGF-β1, thereby promoting the therapeutic effects of MSCs in defect tissue in rats [33]. ESWT can also stimulate the production of certain osteogenic transcription factors in a rat model, for instance, collagen type I, Osterix, Runt-related transcription factor 2, and alkaline phosphatase, leading to the differentiation of BMSCs into osteoblasts [70]. Subsequently, disruption of the membrane due to sound waves and pressure from ESWT induces the generation of superoxide and TGF-β1, leading to the initiation of a signaling pathway that promotes the differentiation of mesenchymal progenitor cells from human umbilical cord blood into osteogenic cells. This process ultimately improves the healing of femoral segmental bone defects in mice with severe combined immunodeficiency disease [71]. In a rat model, a new method of using ESWT along with injecting teriparatide-loaded hydrogel locally enhances the proliferation, migration, and differentiation of osteoporosis-derived bone marrow mesenchymal stem cells (OP-BMSCs) into osteoblasts in vitro, and significantly enhances the healing of segmental bone defects in vivo [72]. To sum up, ESWT has the potential to improve the proliferation and differentiation of stem cells, which can help in the healing of bone defects.

Fracture

A fracture is defined as a disruption of bone continuity and integrity caused by a specific external force [73]. Although most fractures can heal, nonunion is a common complicating disease of fractures. For example, approximately 10% of tibia fractures fail to heal and require additional interventions [74]. Bone reconstruction surgeries rely on the natural presence of osteoprogenitors and MSCs to provide the necessary osteogenic cells. Nevertheless, in certain situations, these cell populations may be insufficient in number, necessitating the recruitment of stimulatory factors to enhance osteoblast quantity and differentiation capabilities [75]. ESWT, a non-invasive therapy, is a potent stimulator of osteoprogenitor cells, such as BMSCs [34], in vivo, which can enhance the proliferation and osteogenic differentiation potential of MSCs in vitro [41, 76,77,78,79]. First of all, ESWT facilitates BMSCs growth and differentiation into osteoprogenitor cells through early O2-mediated induction of TGF-β1 in an animal model [79]. In addition, ESWT can induce hyperpolarization of human bone marrow stem cells (HBMSCs) membrane and transmit osteogenic differentiation signal via the activation of the Ras pathway, thus promoting osteogenic differentiation of HBMSCs [78]. Besides, ESWT induces the release of adenosine triphosphate (ATP) that activates P38 MAPK signaling through P2 × 7 receptors in human MSCs, leading to human MSCs osteogenic differentiation [80]. ESWT can enhance the differentiation of MSCs into osteoblastic lineage by activating different signaling pathways like focal adhesion kinase (FAK), extracellular signal-regulated kinases-1/2 (ERK1/2), and Runt-related transcription factor-2 (Runx2) [81]. Overall, ESWT enhances the quantity of osteoprogenitor cells and their ability to differentiate into bone-forming cells, thus providing an alternative therapeutic tool for bone reconstruction.

Other diseases of the musculoskeletal system

In addition to the aforementioned diseases, ESWT has also shown the potential to promote recovery from other diseases by regulating the behavior of stem cells. First, ESWT shows potential as a treatment for avascular necrosis of the femoral head (ANFH) by enhancing the expression of core-binding factor α1 (Cbfα1) through activation of the Ras-regulated MAPK pathway and boosting ALP activity and osteocalcin (OCN) levels, ultimately promoting the proliferation and osteogenic differentiation of MSCs. Moreover, ESWT can also inhibit MSCs adipogenic differentiation by reducing the expression level of peroxisome proliferator-activated receptor gamma (PPARG), which is an effective method for treating ANFH [82]. Second, the use of ESWT or adipose-derived mesenchymal stem cell (ADMSC) therapy resulted in a significant decrease in myoglobin and creatine phosphokinase levels. The combination of extracorporeal cardiac shock waves (ECSWs) and ADMSCs treatment further reduced the expression of these biomarkers in animals with ischemia-reperfusion injury. This indicates that ECSW and ADMSC treatment may be a viable option for acute rhabdomyolysis patients who do not respond to conventional treatment [83]. Third, ESWT can boost the activity, proliferation, migration, and collagen production of remaining cells in the anterior cruciate ligament, as well as the production of collagen, TGF-β, VEGF, and the modulation of BMSCs proliferation, migration, collagen synthesis, and tendon formation, thus improving graft maturation following anterior cruciate ligament reconstruction [84]. Finally, in a rat model of chronic hind limb ischemia, pretreatment with shock waves aids in attracting circulating EPCs by boosting the levels of stromal cell-derived factor-1 (SDF-1) and VEGF, ultimately enhancing the therapeutic efficacy of EPC for patients with chronic ischemia [35]. In summary, ESWT has a wide range of potential applications as a promising method to modulate stem cell behavior, providing new therapeutic avenues for the treatment of a variety of musculoskeletal diseases Table 1.

Table 1 Application of ESWT on stem cells therapy for musculoskeletal system diseases
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Application of ESWT on stem cells therapy for cardiovascular system diseases

Coronary heart disease

Coronary heart disease (CHD), as the primary cause of death globally, is characterized by the accumulation of atherosclerotic plaque in the coronary arteries, leading to a narrowing of the artery, thus hindering the normal blood flow to the myocardium [85, 86]. Hypoxia-induced damage to endothelial cells is a key factor in the development of angiocardiopathy, such as CHD [87]. Current treatment options, such as percutaneous coronary intervention and coronary artery bypass grafting, have significantly enhanced symptoms and prognosis for most CHD patients. Nevertheless, it remains important to avoid myocardial ischemia and enhance the well-being of individuals who are ineligible for surgery or still suffer from angina pectoris despite receiving the best possible medical or surgical care [88, 89]. EPCs, originating from bone marrow or peripheral blood, can transport to the ischemic heart muscle and transform into fully developed endothelial cells, contributing to the restoration of the injured vascular endothelium and encouraging the formation of new blood vessels [90,91,92]. However, CHD can reduce the quantity and hinder the function of EPCs, thus impeding the process of endothelial repair regulated by EPCs [93, 94]. Therefore, other strategies are required to enhance the quantity and function of EPCs.

ESWT, which is a new and noninvasive method, can improve cardiac muscle ischemia and heart function by improving the function of EPCs [95,96,97,98]. For instance, ESWT can enhance EPCs function in a rat model by triggering the PI3K/Akt/eNOS signaling pathway and reducing EPCs apoptosis after hypoxic injury [99]. In addition, ESWT elevated the expression of VEGF and IL-8 in the heart muscle deprived of oxygen, leading to the proliferation, differentiation and recruitment of endothelial progenitor cells in a medical study. Besides, after undergoing ESWT, patients with CHD experienced relief in clinical symptoms, as well as improvements in their quality of life and exercise endurance [38]. As a consequence, ESWT enhancement of EPCs function in patients with CHD may be a hopeful strategy for the prevention and treatment of ischaemic heart disease.

Acute myocardial infarction

Acute myocardial infarction (AMI) is the most severe and lethal type of CHD [100], which happens when the main branch of the coronary artery is abruptly obstructed, resulting in ischemia or the death of heart muscle cells [101,102,103]. Among the various therapies, stem cell therapy plays a positive role in treating heart ischemia disorder of numerous etiologies, including alleviating ischemic injuries, reducing the severity of angina, and preserving heart function [104,105,106]. Specifically, utilizing bone marrow stem cell treatment can be advantageous in enhancing heart dysfunction resulting from ischemic events or heart infarction [107,108,109]. Yet, the extent of cardiac function improvement after different cell therapies remains limited and inadequate in individuals with heart muscle ischemia or acute myocardial infarction [107,108,109,110,111,112]. Thus, novel and effective therapeutic methods are needed to further promote heart function [113, 114].

During ischemic preconditioning, ESWT enhances the expression of Connexin-43 (Cx43) in cardiomyocyte mitochondria, thereby contributing significantly to the reduction of infarct size [115]. In a rabbit model, the expression of Cx43 and cytochrome C protein in mitochondria can be enhanced by treating bone marrow-derived mononuclear cells (BMDMNCs) with ESWT. Additionally, in a rabbit model, the combination of ESWT with BMDMNCs was found to be more effective than BMDMNC therapy alone in reducing endothelin-1 (ET-1) gene expression and enhancing endothelial nitric oxide synthase (eNOS) gene expression to improve left ventricular (LV) function [116]. The combined application of ESWT and BMDMNCs treatment had a superior effect compared with either ESWT or BMDMNCs treatment in the mini-pig AMI model, including inhibition of heart remodeling, apoptosis and inflammation, decrease in heart infarct size, enhancement of angiogenesis as well as the preservation of heart function [117]. Therefore, ESWT combined with stem cell therapy is a promising therapeutic approach for AMI patients.

Dilated cardiomyopathy

The characteristics of dilated cardiomyopathy (DCM) are LV or biventricular dilation and systolic dysfunction without coronary artery disease, valvular or congenital heart disease [118, 119]. The physiopathological mechanisms of DCM involved aggravative inflammation, oxidative stress, mitochondria (mito) reactive oxygen species production, mito dysfunction [120,121,122,123,124,125,126]. Among these mechanisms, mito dysfunction leads to energy exhaustion because of scar generation and the death of myocardial cells [124,125,126,127,128]. The early direct transplantation of mito into LV cardiac muscle of DCM rats not only preserved the function of LV, but also obviously inhibited recipient cells apoptosis, oxidative stress and further mito injury [129]. However, there are some questions regarding mito transplantation, such as the fact that most transplanted mito seem to remain outside of cells. Hence, other strategies are expected to improve the internalization of transplanted mito [130].

ESWT, as an innovative therapy, enhanced the transfer of external mitochondria into the recipient cells both in vitro and in vivo [131, 132]. Moreover, in DCM rats, ESWT-assisted mitochondrial delivery into ADMSCs was more effective than ESWT alone in promoting angiogenesis and reducing heart DCM injury [133]. Overall, combining ESWT with mitochondrial implantation into ADMSCs could provide advantages for DCM patients, especially those with impaired LV function and resistance to conventional treatments Table 2.

Table 2 Application of ESWT on stem cells therapy for cardiovascular system diseases
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Application of ESWT on stem cells therapy for genitourinary system diseases

Bladder dysfunction

Bladder dysfunction can manifest as urinary incontinence, neurogenic bladder or urinary retention [134], including diabetic bladder dysfunction (DBD) and stress urinary incontinence (SUI) et al. Traditional management approaches for DBD focus on relieving symptoms rather than addressing the potential disorders, making it a refractory condition [135]. The therapeutic methods for SUI such as pelvic floor exercises, electrostimulation, sling and artificial urinary sphincter, have demonstrated unsatisfactory effectiveness at present. Therefore, new and effective treatments are urgently needed to restore normal urethral function for the above mentioned disorders [136].

Stem cell treatment holds promise in the treatment of DBD and SUI due to its ability to promote neurovascular muscle regeneration [137, 138]. ADSCs originate from adipose tissue and are a type of mesenchymal stem cells. Although bladder function can be partially restored through ADSCs differentiation, promoting cell activity after transplantation remains challenging [139]. Therefore, it is crucial to investigate additional approaches to improve the effectiveness of stem cells in treating DBD and SUI.

As a type of physical therapy of modalities, ESWT has been demonstrated to recruit endogenous stem cells to the site of injury [35, 140, 141] and stimulate local stem cells for the treatment of different urological conditions. ESWT induces the movement of both external ADSCs and internal stem cells toward the bladder by increasing the expression of SDF-1 [135, 137]. Furthermore, ESWT can stimulate ADSCs to secrete more VEGF and nerve growth factor (NGF), promoting revascularization and innervation regenerations, thereby ameliorating urinary function in diabetic rats [137]. Cell experiments show that the protein kinase R-like endoplasmic reticulum kinase/activating transcription factor-4 (PERK/ATF4) pathway plays a role in the therapeutic effects of ESWT, promoting the formation of myotubes by rat urethral muscle-derived stem cells in vitro, demonstrating the potential of ESWT to activate muscle-derived stem cells (MDSCs) in their original location, which can improve stress urinary incontinence [142]. In summary, ESWT could improve the efficacy of stem cells in treating bladder dysfunction through various mechanisms.

Renal dysfunction

Renal dysfunction is characterized by a serum creatinine level that has increased by at least 50% in comparison with the initial creatinine level [143]. Renal ischemia-reperfusion injury (IRI) and atherosclerotic renal artery stenosis (ARAS) are frequent contributors to renal impairment [144, 145]. The main pathological feature of both ARAS and IRI is the damage to vascular endothelial cells. As a result, it has become essential to focus on promoting angiogenesis and restoring capillaries density as key goals for therapy [146, 147]. Because there are currently unmet medical needs for the clinical treatments of IRI and ARAS, finding a new and effective solution is necessary [148, 149].

Stem or progenitor cell therapy has been proven effective in improving renal function after renal ischemia [150]. EPCs aid in the formation of small blood vessels and the growth of new blood vessels by moving, sticking, and substituting impaired endothelial cells, ultimately assisting in the reduction of kidney damage [151,152,153]. ESWT could strengthen the above mentioned effects of EPCs. ESWT has been shown to increase capillary density in ischemic kidneys by facilitating the mobilization and homing of EPCs from the bone marrow to the narrowed kidney in pigs with ARAS. This effect is achieved through the upregulation of VEGF and Integrin-1β, as well as the stimulation of SDF-1 release [154]. Moreover, the SDF-1/CXCR7 pathway is regulated by ESWT in IRI kidneys, leading to enhanced recruitment of circulating EPCs, as well as improved IRI [155]. In brief, ESWT effectively enhances the mobilization, recruitment, and homing of EPCs, thereby increasing the reparative capacity in kidney tissue.

Erectile dysfunction

Erectile dysfunction (ED) is a persistent or recurrent dysfunction in men to achieve and/or keep penile erection sufficient in sexual intercourse, which is being diagnosed when symptoms persist for at least 3 months [156]. Diabetes mellitus is a frequent contributor to erectile dysfunction, linked to various pathogenic factors like cavernous angiopathy and autonomic neuropathy [157]. At present, phosphodiesterase-5 inhibitors (PDE5i) medications taken by mouth are seen as the primary therapy for individuals with ED [158, 159]. Nevertheless, some individuals with erectile dysfunction caused by diabetes may not have a positive response to this therapy, underscoring the need for exploring other treatment options [160].

Stem cells are a hopeful choice because they can regenerate themselves and transform into different types of cells, including endothelial cells, cavernous smooth muscle cells, and neurons [161]. Stem cell therapy has shown potential as a viable approach for treating ED, either through local engraftment or paracrine signaling [162]. Rats with ED are treated by transplantation of mesenchymal stem cells, such as BMSCs and ADSCs, which are originating from bone marrow and adipose tissue [163, 164]. However, the disadvantage of this treatment approach is the low survival rate of implanted stem cells [165].

ESWT, a new approach in regenerative medicine, aids in the integration of MSCs and enhances their survival rate, ultimately improving the effectiveness of stem cell therapy for ED [166]. First, ESWT has been shown to enhance the survival rate of transplanted BMSCs in the corpus cavernosum, possibly due to increased expression of SDF-1 and stimulation of angiogenesis in diabetic rats with ED [166]. Second, ESWT induces the upregulation of platelet endothelial cell adhesion molecule (PECAM) and SDF-1 in penile tissues of diabetic rats with ED, facilitating the recruitment of MSCs [27]. Additionally, ESWT can increase the expression of VEGF in diabetic rats with ED. VEGF plays a crucial role in improving erectile function by stimulating the PI3K/AKT/mammalian target of rapamycin (mTOR) and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway [10]. In conclusion, the combined treatment of ESWT and MSC therapy exhibits enhanced regenerative and repair properties compared to MSCT alone, offering promising potential as an effective ED treatment Table 3.

Table 3 Application of ESWT on stem cells therapy for genitourinary system diseases
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Application of ESWT on stem cells therapy for nerve system diseases

Neurological disorders, including central nervou system (CNS) and peripheral nerve system (PNS) diseases, are major contributors to global morbidity and mortality. Surgical and pharmaceutical approaches are common treatment modalities for neurological conditions [16, 167, 168]. However, the effectiveness of these interventions is generally unsatisfactory, highlighting the urgent new therapeutic methods.

Recently, stem cell therapy has emerged as a promising treatment for nervous system disorders [169]. The therapeutic mechanism of stem cell therapy involves inhibiting neuroinflammation, promoting neural differentiation and secreting neurotrophic factors [11]. However, a significant drawback in utilizing stem cells (SCs) for nervous system disorders is their restricted abilities in proliferation, differentiation and migration [170]. To address this challenge, ESWT has emerged as a new and promising method to tackle this challenge by stimulating stem cell migration and differentiation with strong regenerative abilities, aiding in tissue regeneration [171]. ESWT has been shown to have a significant impact on the growth and maturation of neural stem cells (NSCs) through the Wnt/β-catenin pathway in a cerebral ischemia rat model [42], resulting in a higher neuron count and ultimately improving neurological function. Furthermore, ESWT can boost the proliferation of NSCs by increasing PI3K and AKT levels and suppressing the nuclear enriched abundant transcript-1 (NEAT1)-let 7b axis in mice [39, 169]. Moreover, the use of ESWT has been shown to promote the growth of new nerve cells, boost the proliferation and differentiation of NSCs, and ultimately enhance the functioning of the nervous system [172]. In summary, the combination of SCs and ESWT is a promising method to treat nerve system diseases Table 4.

Table 4 Application of ESWT on stem cells therapy for nerve system diseases
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Conclusion and perspectives

ESWT is a non-invasive treatment method with significant therapeutic potential and promising clinical applications across various medical fields. In musculoskeletal system diseases, ESWT can enhance cartilage repair, bone defect healing, and fracture reconstruction, thus expediting the recovery process by modulating stem cell behavior. Within cardiovascular system diseases, ESWT effectively alleviates symptoms of coronary heart disease, reduces infarct size post-acute myocardial infarction, and enhances cardiac function in dilated cardiomyopathy through improving the endothelial progenitor cells (EPCs) and other stem cells. Furthermore, ESWT plays a crucial role in urogenital and neurological diseases by recruiting and activating endogenous stem cells to facilitate tissue repair and regeneration, thereby improving patients’ symptoms and quality of life. In conclusion, ESWT, as an emerging treatment modality, has demonstrated significant efficacy and advantages in treating diverse diseases, offering novel therapeutic options and insights to the medical community. With ongoing research and technological advancements, ESWT is poised to be more widely utilized across various fields, delivering improved treatment outcomes and quality of life for patients.

However, two issues need to be noted. First, the research on the impact of ESWT combined with SCs on systemic diseases is still in the early stages and needs more investigation. Second, ESWT can improve the function of stem cells through different mechanisms, such as tissue regeneration, angiogenesis, anti-inflammation, and stem cell activation and recruitment. However, there is no uniform standard for the parameters of ESWT to enhance the effect of SC treatment, including frequency, intensity, timing, duration, and site of stimulation, which should be investigated further in upcoming research. In conclusion, ESWT is a reliable and promising interventional method to promote the effect of SCs on various diseases, which is worthy of further investigation.

Data availability

Not applicable.

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Acknowledgements

The authors declare that artificial intellegence is not used in this study.

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Author notes

  1. Dongyan Kou, Qingyu Chen and Yujing Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, CNPC Central Hospital, Langfang, 065000, PR China

    Dongyan Kou, Qingyu Chen, Yujing Wang & Xiaobin Tang

  2. Department of Rehabilitation Medicine, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, PR China

    Guangyu Xu, Mingcheng Lei & Feng Zhang

  3. Department of Neurosurgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, China

    Hongbin Ni

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  1. Dongyan Kou
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Contributions

DK, QC, YW, HN, FZ contributed to conception and design of this study; DK, QC, YW, GX, ML, XT, HN, FZ contributed to draft the work or substantively revise it. All authors read and approved the final manuscript.

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Correspondence to Hongbin Ni or Feng Zhang.

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Kou, D., Chen, Q., Wang, Y. et al. The application of extracorporeal shock wave therapy on stem cells therapy to treat various diseases. Stem Cell Res Ther 15, 271 (2024). https://doi.org/10.1186/s13287-024-03888-w

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Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512