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Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells or multipotent stem cells, are heterogeneous cell populations with unique immunomodulatory feature and hematopoietic-supporting capacity. MSCs function through a variety of approaches including paracrine and autocrine, direct- or trans-differentiation, bidirectional immunomodulation, and serving as constitutive microenvironment. Of them, exosomes and microvesicles function as the pivotal vehicle for mediating the ameliorative and therapeutic effect of MSCs toward various recurrent and refractory diseases, such as xerophthalmia, radioactive nasal mucosa injury, acute-on-chronic liver failure (ACLF), dermal chronic ulcers, and intrauterine adhesions. State-of-the-art renewal has also highlighted the promising prospective of MSC-derived exosomes (MSC-exo) and diverse biomaterial composites in regenerative medicine. In this book chapter, we mainly focus on the concept, biological phenotypes, preclinical research, and clinical practice of MSC-derived exosomes (MSC-Exos) and/or biomaterials, which will collectively supply overwhelming new references for the further development of MSC-Exos-based biotherapy and disease diagnosis in future.
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
CAS Key Laboratory of Radiation Technology and Biophysics in Institute of Biology and Hefei Institute of Physical Science, Chinese Academy of Sciences, Hefei, China
Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao, China
Department of General Practice, Affiliated Hospital of Xiangnan University, Chenzhou, China
Co-first authors.
Xiaowei Gao
Department of Otorhinolaryngology, Second Hospital of Tianjin Medical University, Tianjin, China
Co-first authors.
Shixun Ma
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
Co-first authors.
Miao Yu
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
Xianghong Xu
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
Yuanguang Zhao
Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao, China
Shuang Chen
Jiangxi Research Center of Stem Cell Engineering, Jiangxi Health-Biotech Stem Cell Technology Co., Ltd., Shangrao, China
Yonghong Li
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
Xiaonan Yang
Department of Plastic and Reconstructive Surgery and Department of Hemangioma and Vascular Malformation, Plastic Surgery Hospital Affiliated to Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Tiankang Guo
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
Hui Cai
Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Key Gansu Provincial Hospital, Lanzhou, China
*Address all correspondence to: leisheng_zhang@163.com
1. Introduction
Exosomes have been considered as cell-derived nanovesicles, which are indicated in disease diagnosis and treatment via the intercellular transportation of cellular constituents, such as proteins, mRNAs, microRNAs, lipids, and cytokines [1, 2, 3]. Longitudinal studies have indicated the secretion of exosome by mammalian cells and the wide distribution in cellular systems [1]. For instance, Heo et al. reported the effect of exosomes upon atherosclerosis by inducing or inhibiting progression of disease through cell-to-cell communication, which suggested the application in disease diagnosis and treatment [4]. State-of-the-art literatures also highlighted the marked technological advances of exosome-based nanotechnology to bloom the further exploitation of exosome-associated biology, pathology, chemistry, and therapeutics [5]. Despite the small membrane vesicles can be released and generated by a variety of eukaryotic cells, yet one of the major obstacles for potential application of exosomes is the strategies for high-efficient and robust enrichment of large-scale preparation with high quantity [1, 6].
Of the numerous parental cells for exosome enrichment, mesenchymal stem/stromal cells (MSCs) are considered with robust immunomodulatory property and therapeutic potential [7, 8, 9]. Differ from the relative cell types, MSCs are advantaged stem cells with high percentage of mesenchymal-associated biomarker expression (e.g., CD44, CD73, CD90, CD105), whereas with minimal expression of type II major histocompatibility complex (MHC-II) or hematopoietic-related surface marker expression (e.g., CD31, CD34, CD43, CD45) [10, 11, 12]. In this chapter, we summarize the basic and clinical research of MSC-derived exosomes (MSC-exo), including the definition, biological phenotypes and significance, preclinical and clinical investigations, and the concomitant molecular mechanism. Taken together, the contents in this chapter will benefit the further development of MSC-exo-based therapeutic regimens for refractory and recurrent disorder administration in future.
Mesenchymal stem/stromal cells (MSCs), also known as medicinal signaling cells, are unique multipotent stem cells with multi-lineage differentiation capacity and bidirectional immunomodulatory property [13]. Meanwhile, enormous literatures have demonstrated the hematopoietic-supporting effect of MSCs upon the self-renewal and lineage differentiation potential of hematopoietic stem cells (HSCs), which thus play a critical role in physiologic hematopoiesis and hematologic malignancies [14]. Since the first identification from clinical samples in 1968 [15], MSCs of different origins have been consecutively isolated from adult tissues (e.g., bone marrow, adipose tissue, dental pulp) and perinatal tissues (e.g., placenta tissue, amniotic membrane, umbilical cord, amniotic fluid) [16, 17]. Of them, bone marrow-derived MSCs (BM-MSCs) have been considered with the widest range of application, while umbilical cord-derived MSCs (UC-MSCs) have been recognized with the most robust long-term proliferation and immunoregulatory capacity, respectively [13, 18]. As shown by the ClinicalTrials.gov website, over 1400 trials have been registered for a variety of refractory and recurrent disease administration (Figure 1).
Figure 1.
Illustration of MSC-based clinical trials.
To date, MSCs have been considered with various origins, including mesoderm, endoderm, ectoderm, trophoblasts, and neural crest cells (NCCs) [19, 20]. Therewith, MSCs have been recognized as heterogeneous stem cells and show variations in multitudinous biofunctions. Since the year of 2005, pioneering investigators in the field have employed pluripotent stem cells (PSCs) including induced PSCs (iPSCs) and embryonic stem cells (ESCs) for the preparation of MSCs for large-scale application. For instance, Zhang et al. reported the high-efficiency MSC generation from human PSCs (hPSCs) within two weeks by a cell programming strategy, which was accomplished by the combination of a master transcription factor named MSX2 (Msh Homeobox 2) and small molecule cocktails (TGF-β, bFGF, decitabine) [19]. Subsequently, Wei et al. took advantage of two chemical compounds including OICR-9429 (a JAK signal and histone methyltransferase inhibitor) and decitabine (DAC) for the enhanced induction of MSCs from hESCs [21]. Very recently, we reported the high-efficiency MSC induction from hESCs within two weeks via the non-gene-editing cell programming with LLY-507 (a JAK/STAT or BRD4 inhibitor) and AZD5153 (an epigenetic reader domain inhibitor) [10]. Similar to UC-MSCs, hPSC-MSCs revealed superiority in ex vivo proliferation and immunomodulation over the counterparts from diverse adult tissues.
MSCs function via diverse modes of action, including differentiation, immunomodulation, and secretion. Of them, exosomes and small extracellular vesicles (sEVs) are considered as the two major forms of derivatives of MSCs, which thus play a pivotal role in mediating disease diagnosis and treatment [22, 23]. Exosomes are nano-sized sEVs secreted by the parent cells and play a pivotal role in diverse physiological and pathological processes [24]. To date, a variety of components have been identified from exosomes, such as nucleic acids (e.g., mRNAs, microRNAs, tRNAs, circRNAs), proteins (e.g., cytokines, peptides, amino acids, anti-inflammatory factors), lipids, metabolites, and relative bioactive substances [25].
Distinguish from liposomes and nanoparticles, exosomes with endogeneity and heterogeneity reveal unique and extensive advantages in the field of pathologic diagnosis and disease treatment [26]. Exosomes are nanoparticles with a diameter ranging from 50 nm to 200 nm, which are adequate to interact with organelles and relative intracellular vesicles [27, 28]. As a unique nanoscale spherical lipid bilayer vesicles, exosomes exhibit a density of 1.13–1.19 g • mL−1 according to the sucrose density gradient solution [29]. The conception of “exosomes” is firstly proposed by Trams et al. and referred to the vesicles derived from plasma membrane, which is also regarded as the membrane vesicles with 5′-nucleotide enzyme activity. Currently, exosomes are recognized as nano-particles with multitudinous physiological functions, which can be isolated from the exudation and supernatant of various cells and breezily cross the extracellular matrix and blood vessel wall [7, 30]. For instance, a category of exosomal microRNAs have been involved in the pathogenesis and diagnosis of tumors and immune disorders, which are adequate to mediate exosome-inflammasome crosstalk and epithelial mesenchymal transition (EMT), together with chemoresistance and metastasis of tumor cells [27, 30]. In 2021, Patil et al. reported the novel mechanisms of MSC-exo-mediated phagocytosis and opsonization of dying cardiomyocytes during myocardial ischemic injury both in vitro and in vivo [31].
As reviewed by Zhang et al., the ubiquitous exosomes are advantaged cell-free therapeutic products, which are small in size and thus breezily cross the extracellular matrix and blood vessel wall [7]. For instance, MSC-exo have shown considerable safety and therapeutic effects upon various diseases such as atherosclerosis, and acute and chronic wound model [4, 26]. Govindappa and the colleagues found that diabetic milieu were adequate to stimulate RNA-binding proteins like human antigen R (HuR) expression via increasing pro-fibrogenic and inflammatory responses in fibroblasts and cardiac fibrosis mediated by macrophages-derived exosomes [32]. Meanwhile, the chitosan hydrogel has been proved effective in boosting the stability and retention of exosomes enriched from placenta-derived mesenchymal stem cells (P-MSC-exo) and the contents (e.g., proteins, lipid, microRNAs), together with the resultant enhanced efficacy for hindlimb ischemia treatment and remission [12]. As mentioned above, MSC-derived exosomes (MSC-exo) and the relative sEVs have been reported with diverse application prospects in a variety of refractory and recurrent disease administration, yet the large-scale application for disease management is far from satisfaction, which largely attributes to the inherent disadvantages of exosomes, including the low yield, storage stability, low purity, and weak targeting [27].
Biomaterials with tissue compatibility and inflammatory response mainly function via in contact with biological tissue, which are mainly applied in the medical field for tissue engineering or developing artificial organs for regenerative purposes. Generally, biomaterials can be divided into synthetic polymer biomaterials (silicone rubber, polyurethane, polyester, polyacrylonitrile), natural polymer biomaterials (regenerated fibers, chitin, collagen, hyaluronic acid), medical metal materials (titanium and titanium alloys, stainless steel, titanium-nickel memory alloys), inorganic biomedical materials (bioactive ceramics, carbon materials, glass materials), hybrid biomaterials (e.g., cross-linked hybridization of collagen, polyvinyl alcohol), and composite biomaterials (e.g., bioceramics, glass reinforced with glass fibers).
Current progress in materials and cell biology has extensively indicated the superiority of multiple biomaterials for preclinical and clinical application upon diverse relapse and recurrent diseases, and in particular, the composites of biomaterials and MSC-exo for tissue engineering and regenerative purposes attribute to the unique biocompatibility. In details, biomaterials with biocompatible and biodegradable properties are capable of facilitating the efficacy of MSCs or MSC-exo and enhancing their manifestations during anti-tumor immunity by endowing the therapeutic ability of these encapsulated constituents [33, 34, 35]. To date, a variety of biomaterials have been introduced for MSC-exo-based regimens in biomedicine, such as hydrogel acid (HA) (e.g., ε-caprolactone (PCL)/nano-hydroxyapatite (nHA) scaffold, chitosan hydrogel, PCL/nHA + HPCH hybrid scaffolds), gelatin, and nanomaterials [12, 36]. These biomaterials with promising prospective have been proved with the ability to reinforce the biological properties or functions of the encapsulated objectives including MSC-exo [37]. Of them HA and gelatin are considered as the two major forms of extracellular matrix, which are widely distributed in tissues of the body and benefiting the preparation of the compatible hybrid hydrogels by orchestrating the specific composition, scaffold structure, immune microenvironment, and the concomitant physico-chemical property [38, 39]. For example, as reviewed by Celikkin et al. and Xiao et al., Gelatin methacrylate-based hydrogels exhibit preferable properties over other counterparts in tissue engineering and disease administration on the basis of their biofunctionality as well as unique mechanical tenability (e.g., chemical properties, porosity, physical strength, and conductivity) [40, 41]. Similarly, a number of investigators in the field have also observed the hydrogel encapsulation, exosome-loaded thermosensitive hydorgels, and MSC-exo/hydrogel hybrid patch in controlling the release of paracrine factors, enhancing the maintenance of the biological activity, enhancing corneal epithelium regeneration from MSCs and MSC-exos [42, 43, 44].
Longitudinal studies have also suggested the application of multifarious collagens with high biocompatibility is applied as natural scaffolds for tissue engineering, including extracellular matrix (ECM), elastin, proteoglycans, and glycoproteins [45, 46]. For example, the implantation of engineered collagen matrices or resorbable collagen scaffolds has been reported effectively for the remission of meniscus defects by Warth et al. and Patil et al. [47, 48]. Of note, the latest progress has also highlighted the bioprinting of pure collagen or in combination with MSCs and/or MSC-exo for regenerative purposes as well [49]. On the basis of the immunomodulatory properties, MSC-exo have been used as a dermatological nano-therapeutic agent for the administration of oxidative stress-induced skin injury by modulating the NRF2 defense system and H2O2-stimulated epidermal keratinocytes [50].
Nanomaterials are defined by their diameters ranging from 1 nm to 100 nm, together with the facilitating effect upon the permeability and retention of the encapsulated cells or cellular components including MSCs and the derivatives (e.g., exosomes, sEVs) [51]. Nanomaterials, together with the nanostructure-mediated physical signals, have been recognized as splendid sources for mimicking ECM and enhancing the therapeutic effect of MSC-exo, which are tightly orchestrated by activating specific signals [52, 53, 54, 55, 56, 57]. For example, Luo and the colleagues verified the feasibility of MSC-exo for amelioration of the inflammation-induced astrocyte alterations via the Nrf2-NF-κB signaling pathway [58]. Instead, Zhang et al. verified BM-MSC-derived exosomes (BM-MSC-exo) for promoting remyelination and reducing neuroinflammation via inhibiting the TLR2/IRAK1/NF-κB signaling pathway and increasing polarization of M2 phenotype in the demyelinating central nervous system [59]. Additionally, DiStefano et al. took advantage of Lactic-co-Glycolic Acid and the resultant hydrogel-embedded poly microspheres for the efficient delivery of hMSC-derived exosomes and the promotion of bioactive annulus fibrosus repair [60]. Very recently, Geng et al. reported the generation of the multifunctional antibacterial MSC-Exos@CEC-DCMC HG hydrogel (carboxyethyl chitosan-dialdehyde carboxymethyl cellulose) and BM-MSC-exo composite for accelerating diabetic wound healing [61]. Additionally, with the aid of optimized BM-MSC-exo and unique hierarchical scaffolds, Liu et al. demonstrated the application for bone regeneration by modulating the Smad pathway activated by Bmpr2/Acvr2b competitive receptor [62]. As to the underlying molecular mechanism of various biomaterials in MSC-exo-based regimens, various biomaterials function mainly via orchestrating a series of mode of action, including integrating or incorporating with the encapsulated MSC-exo, benefiting the secretion and maintenance of MSC-exo, serving as substrates or scaffolds, and reinforcing the antioxidant property as well [63, 64, 65]. Collectively, biomaterials of different kinds with high biocompatibility have been recognized as momentous components of the formulations for tissue engineering and regenerative medicine [66, 67, 68, 69, 70].
Attributes to the advantaged property, MSC-exo have been extensively explored in clinical trials. According to the ClinicalTrials.gov website (https://www.clinicaltrials.gov/) of National Institute of Health (NIH), a total number of 164 interventional trials have been registered up to February 4th, 2023 (Figure 2). Of them, most are in the phase 1 and phase 2 stages, together with the recruiting status (Table 1). To date, MSC-exo have been involved in numerous disease administration, including respiratory diseases (e.g., COVID-19, acute respiratory distress syndrome), digestive diseases (e.g., perianal fistula with Crohn’s disease, familial hypercholesterolemia, irritable bowel disease, non-alcoholic fatty liver disease), cutaneous diseases (e.g., alopecia, psoriasis, endothelial dysfunction, wounds and injuries, oral mucositis, diabetic foot), vascular diseases (e.g., cerebrovascular disorders, myocardial infarction, myocardial ischemia, myocardial stunning), reproductive diseases (e.g., extreme prematurity, preterm, polycystic ovary syndrome), neurodevelopmental disorders (e.g., neuralgia, refractory depression, anxiety disorders, post-stroke dementia, Alzheimer disease, major depressive disorder, bipolar disorder, mild cognitive impairment, stroke, acute ischemic stroke, Parkinson disease), movement disorders (e.g., knee osteoarthritis, meniscus tear, tibial and knee injuries, arthralgia), endocrine system diseases (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus), immunological disorders (e.g., allergic asthma, severe eosinophilic asthma), and urinary diseases (e.g., chronic kidney failure, bladder cancer, polycystic kidney disease), and even tumors (e.g., metastatic melanoma, colon cancer, non-Hodgkin’s lymphoma, lung cancer, non-small cell lung cancer, metastatic pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, advanced breast cancer, triple negative breast cancer, gynecologic cancer, prostate cancer, intraductal papillary mucinous neoplasm, malignant glioma, advanced hepatocellular carcinoma, acute myeloid leukemia, T-cell lymphoma, squamous cell carcinoma, advanced gastric cancer, colorectal cancer).
Biomaterials and MSC-exo composites are advantaged sources for tissue engineering and regenerative medicine, which hold superiority over other therapeutic regimens attributes to the unique characteristics. In this chapter, we detailed and introduced the basic conception and latest updates of biomaterials and MSC-exo composites for biomedicine, which will collectively facilitate the further development of MSC-exo-based cell-free regimens in future. Of the multitudinous biomaterials, those with preferable tissue compatibility and minimal inflammatory response would reveal more robust application prospect with MSC-exo in future.
The authors would like to thank the members in Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, and Chinese Academy of Sciences Hefei Institute of Physical Science for their kind suggestions. This study was supported by grants from, National Natural Science Foundation of China (82260031, 82160534), Gansu Provincial Hospital Intra-Hospital Research Fund Project (22GSSYB-6, 21GSSYB-8, 20GSSY5-2), The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor (NHCDP2022004, NHCDP2022008, NHCDP2022014), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), Natural Science Foundation of Jiangxi Province (20224BAB206077, 20212BAB216073), Key project funded by Department of Science and Technology of Shangrao City (2020AB002, 2020 K003, 2021F013, 2022AB003), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao (2020G002), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Guiding plan for scientific and technological development of Lanzhou (2019-ZD-102), Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033), Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076), Young Science and Technology Talent Support Project of Gansu Association for Science and Technology (GXH202220530-17), Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415).
2.Yang D, Zhang W, Zhang H, Zhang F, Chen L, Ma L, et al. Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics. Theranostics. 2020;10(8):3684-3707
3.He C, Zheng S, Luo Y, Wang B. Exosome Theranostics: Biology and translational medicine. Theranostics. 2018;8(1):237-255
4.Heo J, Kang H. Exosome-based treatment for atherosclerosis. International Journal of Molecular Sciences. 2022;23(2)
5.Yang B, Chen Y, Shi J. Exosome biochemistry and advanced nanotechnology for next-generation Theranostic platforms. Advanced Materials. 2019;31(2):e1802896
6.Zhang H, Lu J, Liu J, Zhang G, Lu A. Advances in the discovery of exosome inhibitors in cancer. Journal of Enzyme Inhibition and Medicinal Chemistry. 2020;35(1):1322-1330
7.Zhang LS, Yu Y, Yu H, Han ZC. Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases: From bench to bedside. World Journal of Stem Cells. 2021;13(8):1058-1071
8.Zhang X, Yang Y, Zhang L, Lu Y, Zhang Q , Fan D, et al. Mesenchymal stromal cells as vehicles of tetravalent bispecific Tandab (CD3/CD19) for the treatment of B cell lymphoma combined with IDO pathway inhibitor D-1-methyl-tryptophan. Journal of Hematology & Oncology. 2017;10(1):56
9.Zhang Y, Li Y, Li W, Cai J, Yue M, Jiang L, et al. Therapeutic effect of human umbilical cord mesenchymal stem cells at various passages on acute liver failure in rats. Stem Cells International. 2018;2018:7159465
10.Zhang L, Wei Y, Chi Y, Liu D, Yang S, Han Z, et al. Two-step generation of mesenchymal stem/stromal cells from human pluripotent stem cells with reinforced efficacy upon osteoarthritis rabbits by HA hydrogel. Cell & Bioscience. 2021;11(1):6
11.Yu H, Feng Y, Du W, Zhao M, Jia H, Wei Z, et al. Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice. International Immunopharmacology. 2022;113(Pt A):109408
12.Zhang K, Zhao X, Chen X, Wei Y, Du W, Wang Y, et al. Enhanced therapeutic effects of mesenchymal stem cell-derived exosomes with an injectable hydrogel for Hindlimb ischemia treatment. ACS Applied Materials & Interfaces. 2018;10(36):30081-30091
13.Zhao Q , Zhang L, Wei Y, Yu H, Zou L, Huo J, et al. Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease. Stem Cell Research & Therapy. 2019;10(1):354
14.Zhao M, Li L. Regulation of hematopoietic stem cells in the niche. Science China. Life Sciences. 2015;58(12):1209-1215
15.Friedenstein AJ, Petrakova KV, Kurolesova AI. Frolova GP: Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230-247
16.Yao J, Chen N, Wang X, Zhang L, Huo J, Chi Y, et al. Human supernumerary teeth-derived apical papillary stem cells possess preferable characteristics and efficacy on hepatic fibrosis in mice. Stem Cells International. 2020;2020:6489396
17.Du W, Li X, Chi Y, Ma F, Li Z, Yang S, et al. VCAM-1+ placenta chorionic villi-derived mesenchymal stem cells display potent pro-angiogenic activity. Stem Cell Research & Therapy. 2016;7:49
18.Wei Y, Zhang L, Chi Y, Ren X, Gao Y, Song B, et al. High-efficient generation of VCAM-1(+) mesenchymal stem cells with multidimensional superiorities in signatures and efficacy on aplastic anaemia mice. Cell Proliferation. 2020;53(8):e12862
19.Zhang L, Wang H, Liu C, Wu Q , Su P, Wu D, et al. MSX2 initiates and accelerates mesenchymal stem/stromal cell specification of hPSCs by regulating TWIST1 and PRAME. Stem Cell Reports. 2018;11(2):497-513
20.Jiang B, Yan L, Wang X, Li E, Murphy K, Vaccaro K, et al. Concise review: Mesenchymal stem cells derived from human pluripotent cells, an unlimited and quality-controllable source for therapeutic applications. Stem Cells. 2019;37(5):572-581
21.Wei Y, Hou H, Zhang L, Zhao N, Li C, Huo J, et al. JNKi- and DAC-programmed mesenchymal stem/stromal cells from hESCs facilitate hematopoiesis and alleviate hind limb ischemia. Stem Cell Research & Therapy. 2019;10(1):186
22.Fu X, Liu G, Halim A, Ju Y, Luo Q , Song AG. Mesenchymal stem cell migration and tissue repair. Cell. 2019;8(8)
23.Liu H, Li R, Liu T, Yang L, Yin G, Xie Q. Immunomodulatory effects of mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles in rheumatoid arthritis. Frontiers in Immunology. 1912;2020:11
24.Lai JJ, Chau ZL, Chen SY, Hill JJ, Korpany KV, Liang NW, et al. Exosome processing and characterization approaches for research and technology development. Advanced Science (Weinh). 2022;9(15):e2103222
25.Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478)
26.Wu P, Zhang B, Shi H, Qian H, Xu W. MSC-exosome: A novel cell-free therapy for cutaneous regeneration. Cytotherapy. 2018;20(3):291-301
27.Zhang Y, Bi J, Huang J, Tang Y, Du S, Li P. Exosome: A review of its classification, isolation techniques, storage, diagnostic and targeted therapy applications. International Journal of Nanomedicine. 2020;15:6917-6934
28.Pegtel DM, Gould SJ. Exosomes. Annual Review of Biochemistry. 2019;88:487-514
29.Miao W, Song B, Shi B, Wan Q , Lv Q , Chen H, et al. Immune thrombocytopenia plasma-derived exosomes impaired megakaryocyte and platelet production through an apoptosis pathway. Thrombosis and Haemostasis. 2021;121(4):495-505
30.Noonin C, Thongboonkerd V. Exosome-inflammasome crosstalk and their roles in inflammatory responses. Theranostics. 2021;11(9):4436-4451
31.Patil M, Saheera S, Dubey PK, Kahn-Krell A, Kumar Govindappa P, Singh S, et al. Novel mechanisms of exosome-mediated phagocytosis of dead cells in injured heart. Circulation Research. 2021;129(11):1006-1020
32.Govindappa PK, Patil M, Garikipati VNS, Verma SK, Saheera S, Narasimhan G, et al. Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart. The FASEB Journal. 2020;34(2):2238-2251
33.Koshy ST, Mooney DJ. Biomaterials for enhancing anti-cancer immunity. Current Opinion in Biotechnology. 2016;40:1-8
35.Alvarez Echazu MI, Perna O, Olivetti CE, Antezana PE, Municoy S, Tuttolomondo MV, et al. Recent advances in synthetic and natural biomaterials-based therapy for bone defects. Macromolecular Bioscience. 2022;22(4):e2100383
36.Ji X, Yuan X, Ma L, Bi B, Zhu H, Lei Z, et al. Mesenchymal stem cell-loaded thermosensitive hydroxypropyl chitin hydrogel combined with a three-dimensional-printed poly(epsilon-caprolactone) /nano-hydroxyapatite scaffold to repair bone defects via osteogenesis, angiogenesis and immunomodulation. Theranostics. 2020;10(2):725-740
37.Yang J, Zhang YS, Yue K, Khademhosseini A. Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomaterialia. 2017;57:1-25
38.Velasco-Rodriguez B, Diaz-Vidal T, Rosales-Rivera LC, Garcia-Gonzalez CA, Alvarez-Lorenzo C, Al-Modlej A, et al. Hybrid Methacrylated Gelatin and hyaluronic acid hydrogel scaffolds. Preparation and systematic characterization for prospective tissue engineering applications. International Journal of Molecular Sciences. 2021;22(13)
39.Madhusudanan P, Raju G, Shankarappa S. Hydrogel systems and their role in neural tissue engineering. Journal of Royal Society Interface. 2020;17(162):20190505
40.Xiao S, Zhao T, Wang J, Wang C, Du J, Ying L, et al. Gelatin methacrylate (GelMA)-based hydrogels for cell transplantation: An effective strategy for tissue engineering. Stem Cell Reviews and Reports. 2019;15(5):664-679
41.Celikkin N, Mastrogiacomo S, Jaroszewicz J, Walboomers XF, Swieszkowski W. Gelatin methacrylate scaffold for bone tissue engineering: The influence of polymer concentration. Journal of Biomedical Materials Research. Part A. 2018;106(1):201-209
42.Khayambashi P, Iyer J, Pillai S, Upadhyay A, Zhang Y, Tran SD. Hydrogel encapsulation of mesenchymal stem cells and their derived exosomes for tissue engineering. International Journal of Molecular Sciences. 2021;22(2)
43.Tang Q , Lu B, He J, Chen X, Fu Q , Han H, et al. Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration. Biomaterials. 2022;280:121320
44.Han M, Yang H, Lu X, Li Y, Liu Z, Li F, et al. Three-dimensional-cultured MSC-derived exosome-hydrogel hybrid microneedle Array patch for spinal cord repair. Nano Letters. 2022;22(15):6391-6401
45.Blackstone BN, Gallentine SC, Powell HM. Collagen-based electrospun materials for tissue engineering: A systematic review. Bioengineering (Basel). 2021;8(3)
46.Rezvani Ghomi E, Nourbakhsh N, Akbari Kenari M, Zare M, Ramakrishna S. Collagen-based biomaterials for biomedical applications. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2021;109(12):1986-1999
47.Warth RJ, Rodkey WG. Resorbable collagen scaffolds for the treatment of meniscus defects: A systematic review. Arthroscopy. 2015;31(5):927-941
48.Patil VA, Masters KS. Engineered collagen matrices. Bioengineering (Basel). 2020;7:4
49.Lee JM, Suen SKQ , Ng WL, Ma WC, Yeong WY. Bioprinting of collagen: Considerations, potentials, and applications. Macromolecular Bioscience. 2021;21(1):e2000280
50.Wang T, Jian Z, Baskys A, Yang J, Li J, Guo H, et al. MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Biomaterials. 2020;257:120264
51.Stater EP, Sonay AY, Hart C, Grimm J. The ancillary effects of nanoparticles and their implications for nanomedicine. Nature Nanotechnology. 2021;16(11):1180-1194
52.Zhao C, Tan A, Pastorin G, Ho HK. Nanomaterial scaffolds for stem cell proliferation and differentiation in tissue engineering. Biotechnology Advances. 2013;31(5):654-668
53.Hu B, Cheng Z, Liang S. Advantages and prospects of stem cells in nanotoxicology. Chemosphere. 2022;291(Pt 2):132861
54.Mahapatra C, Lee R, Paul MK. Emerging role and promise of nanomaterials in organoid research. Drug Discovery Today. 2022;27(3):890-899
55.Liu G, Zhou Y, Zhang X, Guo S. Advances in hydrogels for stem cell therapy: Regulation mechanisms and tissue engineering applications. Journal of Materials Chemistry B. 2022;10(29):5520-5536
56.Hofmann MC. Stem cells and nanomaterials. Advances in Experimental Medicine and Biology. 2014;811:255-275
57.Kong Y, Duan J, Liu F, Han L, Li G, Sun C, et al. Regulation of stem cell fate using nanostructure-mediated physical signals. Chemical Society Reviews. 2021;50(22):12828-12872
58.Xian P, Hei Y, Wang R, Wang T, Yang J, Li J, et al. Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics. 2019;9(20):5956-5975
59.Zhang J, Buller BA, Zhang ZG, Zhang Y, Lu M, Rosene DL, et al. Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system. Experimental Neurology. 2022;347:113895
60.DiStefano TJ, Vaso K, Panebianco CJ, Danias G, Chionuma HN, Kunnath K, et al. Hydrogel-embedded poly(lactic-co-glycolic acid) microspheres for the delivery of hMSC-derived exosomes to promote bioactive annulus Fibrosus repair. Cartilage. 2022;13(3):1947
61.Geng X, Qi Y, Liu X, Shi Y, Li H, Zhao L. A multifunctional antibacterial and self-healing hydrogel laden with bone marrow mesenchymal stem cell-derived exosomes for accelerating diabetic wound healing. Biomaterial Advance. 2022;133:112613
62.Liu A, Lin D, Zhao H, Chen L, Cai B, Lin K, et al. Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway. Biomaterials. 2021;272:120718
63.Tian H, Yuan L, Song Y, Deng J, Qi XW. A review of recent advances in nanomaterial-based stem cell therapy and the corresponding risks. Current Stem Cell Research & Therapy. 2022;17(3):195-206
64.Pinho S, Macedo MH, Rebelo C, Sarmento B, Ferreira L. Stem cells as vehicles and targets of nanoparticles. Drug Discovery Today. 2018;23(5):1071-1078
65.Shi M, Xu Q , Ding L, Xia Y, Zhang C, Lai H, et al. Cell infiltrative inner connected porous hydrogel improves neural stem cell migration and differentiation for functional repair of spinal cord injury. ACS Biomaterials Science & Engineering. 2022;8(12):5307-5318
66.Rochlin DH, Inchauste S, Zelones J, Nguyen DH. The role of adjunct nanofibrillar collagen scaffold implantation in the surgical management of secondary lymphedema: Review of the literature and summary of initial pilot studies. Journal of Surgical Oncology. 2020;121(1):121-128
67.Sharma S, Rai VK, Narang RK, Markandeywar TS. Collagen-based formulations for wound healing: A literature review. Life Sciences. 2022;290:120096
68.Murshed M. Mechanism of bone mineralization. Cold Spring Harbour Perspective Medicine. 3 Dec 2018;8(12):a031229
69.Huang J, Heng S, Zhang W, Liu Y, Xia T, Ji C, et al. Dermal extracellular matrix molecules in skin development, homeostasis, wound regeneration and diseases. Seminars in Cell & Developmental Biology. 2022;128:137-144
70.Brett D. A review of collagen and collagen-based wound dressings. Wounds. 2008;20(12):347-356
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