McCulloch, E. A. & Till, J. E. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat. Res. 13, 115–125 (1960).
Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).
Friedenstein, A. J., Chailakhyan, R. K., Latsinik, N. V., Panasyuk, A. F. & Keiliss-Borok, I. V. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17, 331–340 (1974).
Horwitz, E. M. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc. Natl Acad. Sci. USA 99, 8932–8937 (2002).
Le Blanc, K. et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579–1586 (2008).
Lee, R. H. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5, 54–63 (2009).
Luger, D. et al. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ. Res. 120, 1598–1613 (2017).
Carr, M. J. et al. Mesenchymal precursor cells in adult nerves contribute to mammalian tissue repair and regeneration. Cell Stem Cell 24, 240–56 e9 (2019).
Gao, F. et al. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 7, e2062 (2016).
Varderidou-Minasian, S. & Lorenowicz, M. J. Mesenchymal stromal/stem cell-derived extracellular vesicles in tissue repair: challenges and opportunities. Theranostics 10, 5979–5997 (2020).
Zaborowski, M. P., Balaj, L., Breakefield, X. O. & Lai, C. P. Extracellular vesicles: composition, biological relevance, and methods of study. Bioscience 65, 783–797 (2015).
He, C., Zheng, S., Luo, Y. & Wang, B. Exosome theranostics: biology and translational medicine. Theranostics 8, 237–255 (2018).
Zhu, L. P. et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics 8, 6163–6177 (2018).
Eirin, A. et al. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int 92, 114–124 (2017).
Zhu, Y. G. et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 32, 116–125 (2014).
Shigemoto-Kuroda, T. et al. MSC-derived extracellular vesicles attenuate immune responses in two autoimmune murine models: type 1 diabetes and uveoretinitis. Stem Cell Rep. 8, 1214–1225 (2017).
Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).
Fuchs, Y. & Steller, H. Programmed cell death in animal development and disease. Cell 147, 742–758 (2011).
Nagata, S., Hanayama, R. & Kawane, K. Autoimmunity and the clearance of dead cells. Cell 140, 619–630 (2010).
Taylor, R. C., Cullen, S. P. & Martin, S. J. Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell Biol. 9, 231–241 (2008).
Caruso, S. & Poon, I. K. H. Apoptotic cell-derived extracellular vesicles: more than just debris. Front Immunol. 9, 1486 (2018).
Chen, H. et al. Extracellular vesicles from apoptotic cells promote TGFbeta production in macrophages and suppress experimental colitis. Sci. Rep. 9, 5875 (2019).
Laing, A. G., Riffo-Vasquez, Y., Sharif-Paghaleh, E., Lombardi, G. & Sharpe, P. T. Immune modulation by apoptotic dental pulp stem cells in vivo. Immunotherapy 10, 201–211 (2018).
Kou, X. et al. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci. Transl. Med. 10, eaai8524 (2018).
Zernecke, A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal 2, ra81 (2009).
Liu, J. et al. Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages. Stem Cell Res. Ther. 11, 507 (2020).
Liu, Y. et al. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha. Nat. Med. 17, 1594–1601 (2011).
Liu, S. et al. Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis. J. Invest. Dermatol. 134, 2648–2657 (2014).
Galleu, A. et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med. 9, eaam7828 (2017).
Liu, H. et al. Donor MSCs release apoptotic bodies to improve myocardial infarction via autophagy regulation in recipient cells. Autophagy 16, 2140–2155 (2020).
Chang, C. L. et al. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in rat sepsis syndrome induced by cecal puncture and ligation. J. Transl. Med. 10, 244 (2012).
Chen, H. H. et al. Additional benefit of combined therapy with melatonin and apoptotic adipose-derived mesenchymal stem cell against sepsis-induced kidney injury. J. Pineal. Res. 57, 16–32 (2014).
Liu, D. et al. Circulating apoptotic bodies maintain mesenchymal stem cell homeostasis and ameliorate osteopenia via transferring multiple cellular factors. Cell Res. 28, 918–933 (2018).
Dou, G. et al. Chimeric apoptotic bodies functionalized with natural membrane and modular delivery system for inflammation modulation. Sci. Adv. 6, eaba2987 (2020).
Gronthos, S., Mankani, M., Brahim, J., Robey, P. G. & Shi, S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc. Natl Acad. Sci. USA 97, 13625–13630 (2000).
Miura, M. et al. SHED: stem cells from human exfoliated deciduous teeth. Proc. Natl Acad. Sci. USA 100, 5807–5812 (2003).
Seo, B.-M. et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 364, 149–155 (2004).
Weiss, M. L. & Troyer, D. L. Stem cells in the umbilical cord. Stem Cell Rev. 2, 155–162 (2006).
Bi, Y. et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat. Med. 13, 1219–1227 (2007).
Zhang, Q. et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J. Immunol. 183, 7787–7798 (2009).
Zuk, P. A. et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211–228 (2001).
Shi, S. & Gronthos, S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Min. Res. 18, 696–704 (2003).
Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).
Feng, J., Mantesso, A., De Bari, C., Nishiyama, A. & Sharpe, P. T. Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proc. Natl Acad. Sci. USA 108, 6503–6508 (2011).
Achilleos, A. & Trainor, P. A. Neural crest stem cells: discovery, properties and potential for therapy. Cell Res. 22, 288–304 (2012).
Kaukua, N. et al. Glial origin of mesenchymal stem cells in a tooth model system. Nature 513, 551–554 (2014).
Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838–3843 (2002).
Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).
Puissant, B. et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br. J. Haematol. 129, 118–129 (2005).
Nauta, A. J. & Fibbe, W. E. Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499–3506 (2007).
Ren, G. et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2, 141–150 (2008).
Yamaza, T. et al. Immunomodulatory properties of stem cells from human exfoliated deciduous teeth. Stem Cell Res. Ther. 1, 5 (2010).
Boiret, N. et al. Characterization of nonexpanded mesenchymal progenitor cells from normal adult human bone marrow. Exp. Hematol. 33, 219–225 (2005).
Kortesidis, A. et al. Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 105, 3793–3801 (2005).
Aslan, H. et al. Osteogenic differentiation of noncultured immunoisolated bone marrow-derived CD105+ cells. Stem Cells 24, 1728–1737 (2006).
Lv, F. J., Tuan, R. S., Cheung, K. M. & Leung, V. Y. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32, 1408–1419 (2014).
Zhao, H. et al. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 14, 160–173 (2014).
Vidovic, I. et al. alphaSMA-expressing perivascular cells represent dental pulp progenitors in vivo. J. Dent. Res. 96, 323–330 (2017).
Lendahl, U., Zimmerman, L. B. & McKay, R. D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585–595 (1990).
Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G. & Morrison, S. J. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15, 154–168 (2014).
Liu, Y. et al. PD-1 is required to maintain stem cell properties in human dental pulp stem cells. Cell Death Differ. 25, 1350–1360 (2018).
Galipeau, J. & Sensebe, L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22, 824–833 (2018).
Chen, C. et al. Efficacy of umbilical cord-derived mesenchymal stem cell-based therapy for osteonecrosis of the femoral head: a three-year follow-up study. Mol. Med. Rep. 14, 4209–4215 (2016).
Matas, J. et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl. Med. 8, 215–224 (2019).
Xuan, K. et al. Deciduous autologous tooth stem cells regenerate dental pulp after implantation into injured teeth. Sci. Transl. Med. 10, eaaf3227 (2018).
Kebriaei, P. et al. A phase 3 randomized study of remestemcel-L versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease. Biol. Blood Marrow Transpl. 26, 835–844 (2020).
Yuan, X. et al. Mesenchymal stem cell therapy induces FLT3L and CD1c(+) dendritic cells in systemic lupus erythematosus patients. Nat. Commun. 10, 2498 (2019).
Riordan, N. H. et al. Clinical feasibility of umbilical cord tissue-derived mesenchymal stem cells in the treatment of multiple sclerosis. J. Transl. Med. 16, 57 (2018).
Williams, A. R. & Hare, J. M. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ. Res. 109, 923–940 (2011).
Kfoury, Y. & Scadden, D. T. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell 16, 239–253 (2015).
Kim, S. G. et al. Dentin and dental pulp regeneration by the patient’s endogenous cells. Endod. Top. 28, 106–117 (2013).
Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 11, 367–368 (2005).
Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).
Kinnaird, T. et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109, 1543–1549 (2004).
Choi, H., Lee, R. H., Bazhanov, N., Oh, J. Y. & Prockop, D. J. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 118, 330–338 (2011).
Ling, W. et al. Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment. Cancer Res. 74, 1576–1587 (2014).
Wang, G. et al. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death Differ. 25, 1209–1223 (2018).
Aggarwal, S. & Pittenger, M. F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).
Du, L. et al. IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties. Cell Metab. 29, 1363–75 e8 (2019).
Liu, S. et al. MSC transplantation improves osteopenia via epigenetic regulation of notch signaling in lupus. Cell Metab. 22, 606–618 (2015).
Chen, C. et al. Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis. Cell Res. 27, 559–577 (2017).
Yang, R. et al. IFN-gamma promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b. Cell Death Dis. 11, 603 (2020).
Mayourian, J. et al. Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility. Circ. Res. 122, 933–944 (2018).
Phinney, D. G. et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat. Commun. 6, 8472 (2015).
Fuchs, Y. & Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 16, 329–344 (2015).
Doerflinger, M. et al. Flexible usage and interconnectivity of diverse cell death pathways protect against intracellular infection. Immunity 53, 533–47 e7 (2020).
Zhang, Y., Chen, X., Gueydan, C. & Han, J. Plasma membrane changes during programmed cell deaths. Cell Res 28, 9–21 (2018).
Coleman, M. L. et al. Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat. Cell Biol. 3, 339–345 (2001).
Sisirak, V. et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell 166, 88–101 (2016).
Cabral-Piccin, M. P. et al. Apoptotic CD8 T-lymphocytes disable macrophage-mediated immunity to Trypanosoma cruzi infection. Cell Death Dis. 7, e2232 (2016).
Taylor, J. J., Pape, K. A., Steach, H. R. & Jenkins, M. K. Humoral immunity. Apoptosis and antigen affinity limit effector cell differentiation of a single naive B cell. Science 347, 784–787 (2015).
Morris, A. B. et al. Signaling through the inhibitory Fc receptor FcgammaRIIB induces CD8(+) T cell apoptosis to limit T cell immunity. Immunity 52, 136–50 e6 (2020).
Rodriguez-Manzanet, R. et al. T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice. Proc. Natl Acad. Sci. USA 107, 8706–8711 (2010).
Herrmann, M. et al. Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41, 1241–1250 (1998).
Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001).
Kawane, K. et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443, 998–1002 (2006).
Berda-Haddad, Y. et al. Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1alpha. Proc. Natl Acad. Sci. USA 108, 20684–20689 (2011).
Wickman, G. R. et al. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 20, 1293–1305 (2013).
Fogarty, C. E. & Bergmann, A. Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease. Cell Death Differ. 24, 1390–1400 (2017).
Chera, S. et al. Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev. Cell 17, 279–289 (2009).
Gupta, K. H. et al. Apoptosis and compensatory proliferation signaling are coupled by CrkI-containing microvesicles. Dev. Cell 41, 674–84 e5 (2017).
Brock, C. K. et al. Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance. Nat. Commun. 10, 1044 (2019).
Koren, E. et al. ARTS mediates apoptosis and regeneration of the intestinal stem cell niche. Nat. Commun. 9, 4582 (2018).
Iimuro, Y. et al. NFkappaB prevents apoptosis and liver dysfunction during liver regeneration. J. Clin. Invest 101, 802–811 (1998).
Malato, Y. et al. NF-kappaB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice. Gastroenterology 143, 1597–608 e11 (2012).
Neumann, B. et al. EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517, 219–222 (2015).
Perez-Garijo, A., Fuchs, Y. & Steller, H. Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. Elife 2, e01004 (2013).
Li, Y. & Lin, F. Mesenchymal stem cells are injured by complement after their contact with serum. Blood 120, 3436–3443 (2012).
Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 10, 544–555 (2012).
Catalano, M. & O’Driscoll, L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors. J. Extracell. Vesicles 9, 1703244 (2020).
Park, S. J. et al. Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns. Proc. Natl Acad. Sci. USA 115, E11721–E11730 (2018).
Atkin-Smith, G. K. et al. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat. Commun. 6, 7439 (2015).
Poon, I. K. et al. Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature 507, 329–334 (2014).
Poon, I. K. H. et al. Moving beyond size and phosphatidylserine exposure: evidence for a diversity of apoptotic cell-derived extracellular vesicles in vitro. J. Extracell. Vesicles 8, 1608786 (2019).
Lleo, A. et al. Shotgun proteomics: identification of unique protein profiles of apoptotic bodies from biliary epithelial cells. Hepatology 60, 1314–1323 (2014).
Dieude, M. et al. The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection. Sci. Transl. Med. 7, 318ra200 (2015).
Xie, Y. et al. Tumor apoptotic bodies inhibit CTL responses and antitumor immunity via membrane-bound transforming growth factor-beta1 inducing CD8+ T-cell anergy and CD4+ Tr1 cell responses. Cancer Res. 69, 7756–7766 (2009).
Frleta, D. et al. HIV-1 infection-induced apoptotic microparticles inhibit human DCs via CD44. J. Clin. Invest 122, 4685–4697 (2012).
Ma, Y. et al. Autophagy controls mesenchymal stem cell properties and senescence during bone aging. Aging Cell 17, e12709 (2018).
Cen, S. et al. Autophagy enhances mesenchymal stem cell-mediated CD4(+) T cell migration and differentiation through CXCL8 and TGF-beta1. Stem Cell Res. Ther. 10, 265 (2019).
Regmi, S. et al. Enhanced viability and function of mesenchymal stromal cell spheroids is mediated via autophagy induction. Autophagy 2020: 1−20.
Chen, Y. et al. Mesenchymal stromal cells directly promote inflammation by canonical NLRP3 and non-canonical caspase-11 inflammasomes. EBioMedicine 32, 31–42 (2018).
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).