Into the Eyes of Bone Marrow-Derived Mesenchymal Stem Cells Therapy
for Myocardial Infarction and Other Diseases
Ming Yang1,3, Zheng Zhang2 and Taohong Hu2*
1School of Basic Medical Sciences, Taishan Medical University, Taian, Shandong, China
2Department of Cardiology, The General Hospital of the PLA Rocket Force, Beijing, China
3Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- *Corresponding Author:
- Taohong Hu
Department of Cardiology
The General Hospital of the PLA Rocket Force, Beijing
Tel: +86215474 0000
E-mail: [email protected]
Received date: Mar 28, 2017; Accepted date: Apr 19, 2017; Published date: Apr 22, 2017
Citation: Yang M, Zhang Z, Hu T (2017) Into the Eyes of Bone Marrow-Derived Mesenchymal Stem Cells Therapy for Myocardial Infarction and Other Diseases. J Cell Sci Ther 8: 266. doi:10.4172/2157-7013. 1000266
Copyright: © 2017 Yang M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Visit for more related articles at Journal of Cell Science & Therapy
Applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been documented for diseases occur in the sports system, the central nervous system, the cardiovascular system etc. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency. Although the autophagy theory has been reported, the underlying mechanisms are still poorly understood. Isolation and culture methods of mesenchymal stem cells are currently concentrate on four ways. Overall, BM-MSCs have both important research significance and clinical application value in cell replacement therapy, gene therapy and reconstruction of tissues as well as organs especially for myocardial infarction. In this article, we review the biological characteristics of BM-MSCs and its research progress especially in myocardial infarction.
Autophagy; Bone marrow-mesenchymal stem cells; Apoptosis; Hypoxia; signal transduction pathways; Myocardial infarction
Bone marrow mesenchymal stem cells (BM-MSCs) are mesoderm derived stem cells, which mainly exist in the interstitial connective tissue. Bone marrow tissue has the most abundant content of BMMSCs. Due to characteristic of self-renewal, proliferation and multidirectional differentiation in appropriate micro environment, BMMSCs have the potential to promote the repair of tissue injury. In view of the advantages of BM-MSCs which are easy to obtain, cultivate, and they have low immune original, which can survival for a long-term in the host and easy for exogenous gene transfer as well as long-term expression, BM-MSCs have been widely used in the field of tissue engineering, cell transplantation, gene therapy, and organ transplantation. Studies shown that the surface antigen phenotype of mesenchymal stem cells was not single but had the characteristics of mesenchymal, endothelial and muscle cells. Besides, immunohistochemistry and flow cytometry revealed that SH2, SH3, CD71, CD29, CD44, CD90, and CD120A were all positive expressed, which can be generally used to identify and amplify the mesenchymal stem cells . Recent studies showed that BM-MSCs could be used in the clinical treatment of autoimmune diseases, degenerative diseases and hypoxic ischemic brain damage [2,3]. Bone marrow not only contains hematopoietic stem cells which can develop and differentiate into all types of blood cells but also has mesenchymal stem cells which can produce non-hematopoietic tissues. Some of articles also called them stick wall cells or fibroblast colony forming units as they relatively easy to adherent and form into fibroblast like clones [4-8]. Moreover, as BM-MSCs come from the supporting structure of the bone marrow, they can act as feeder layer to support growth of hematopoietic stem cells. Therefore BM-MSCs are also called bone marrow stromal cells. In view of the following features of bone marrow which has aroused people's interest [1,9,10]. Furthermore, BM-MSCs can act as support hematopoietic cells, promoting the growth of hematopoietic stem cells. Above all, BM-MSCs have broad application prospects in tissue engineering, cell transplantation and gene therapy because of the advantages of easy separation, amplification and easy operation in vitro and in vivo [11-14]. Taken together, BM-MSCs have important research significance and clinical application value in cell replacement therapy, gene therapy and tissue regeneration. In this article, we review the latest progress, limitation as well as clinical application of BM-MSCs.
How to obtain BM-MSCs?
BM-MSCs are obtained mainly from bone marrow aspiration, while human BM-MSCs are generally drawn from the anterior superior iliac spine . They are also available from the tibia, femur, sternum, lumbar spine. The acquisition sites of BM-MSCs in large animals are the same as humans, however, rabbits’ BM-MSCs need to be extracted in the middle of the tibia or femur bone marrow [16-18]. The proportion of BM-MSCs nucleated cell population accounts for less than 0.000 1%, however they can easily be isolated and expanded by using certain cell culture techniques . Stro-1 monoclonal antibody is usually used to isolate BM-MSCs which grow by attaching to the wall in laminin adhesion culture plate with low concentration of serum and CD45-/A-glycoproteins [6,7,19]. In the past, BM-MSCs isolation methods were mainly concentrated on density gradient centrifugation method, differential adherence screening method, flow cytometry sorting method as well as immune beads method . However, high purity of BM-MSCs cannot be obtained by the four kinds of separation methods as described above. Nowadays, selecting the appropriate factor based on different reactivity of BM-MSCs to growth factors, to stimulate the proliferation, obtaining a higher proportion the mesenchymal stem cells has been regarded as a more accurate isolation method. Meanwhile, the new method of using 3 microns’ diameter plastic petri dish to screen BM-MSCs, whose homogeneity are greater than 98%, with capacity of proliferation, self-renewal and have the potential to differentiate into bone, fat, cartilage tissue differentiation nature [11,21-27]. Overall, currently methods are various among laboratories in the world and further standardization of the BM-MSCs’ separation process is still needed in-depth study according to their biological characteristics and mechanisms.
Application of BM-MSCs: Update
Based on its far-reaching biological effects, there are increasingly number of researches and exciting discoveries in BM-MSCs since 1993(NCBI search result). Up to now, applications of BM-MSCs towards cells, animals and clinical tests have been came down to diseases occurred in the sports system, the central nervous system, the cardiovascular system, the respiratory systemthe digestive system, the urinary system etc. (Figure 1). Among these systems, researches about the sports system and the central nerves system account for a significant proportion. It’s interesting to note that there are 1 papers tried to treat cancer by using BM-MSCs, which has the great significance as most therapies toward cancers have various kinds of severe complications in patients .
Figure 1: Summary of potential of various preventive and therapeutic effects of BM-MSCs.
Autophagy and apoptosis in the BM-MSCs therapy towards myocardial infarction
Autophagy is a process of intracellular bulk degradation in which cytoplasmic components including organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/ vacuole for degradation [29,30]. There are three primary forms of autophagy: chaperone-mediated autophagy, microautophagy and macroautophagy [29-33]. During the process of macroautophagy, the sequestering vesicles, termed autophagosomes, fuse with the lysosome or vacuole resulting in the delivery of an inner vesicle (autophagic body) into the lumen of the degradative compartment [34-36].
Nowadays, one of the highest incidence and fatality rate of clinical disease is myocardial infarction(MI) [37-40]. Numerous studies have been proved BM-MSCs is an emerging effective therapy to the disease. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency, whereas, the underlying mechanism is still poorly understood . Autophagy, a highly-conserved process of cellular degradation, is required for maintaining homeostasis and normal function including MI  (Figure 2).
Figure 2: Number of papers that report effects of BM-MSCs in various systems between January 2012 and February 2017.
Actually, when it comes to the role of autophagy on cell, it is still a controversial issue according to the present study [16,43-46]. There is evidence demonstrated that autophagy can either protect cells or contribute to cell death depend on the intensity of stimulus. Autophagy at basal levels is involved in maintaining normal function in various organisms. Hence, autophagy has been generally considered as a protective cellular response against various stresses. Previous studies have demonstrated that modest autophagy induced by sublethal hypoxic preconditioning can increase cell survival and inhibit extensive apoptosis [6,47-49].
Conversely, other studies also suggested that extensive and prolonged autophagy may be a promoter of apoptosis, leading to cell death as type II programmed cell death. Such discrepancy may be attributed to differences in hypoxic treatment protocol. Our previous studies adopted hypoxia (1% O2)/serum deprivation injury for 24h to mimic ischemic microenvironment in vivo . However, Liu et.al. performed hypoxic preconditioning with 5% O2 for 6h . The comparation results showed that autophagy is paradoxical that can both protect and impair cell survival depending on the environment. Therefore, the different stress or anaerobic injury may result in the disparate effects of autophagy on MSCs.
Regulating autophagic activity may be a potential optimizing target for promoting BM-MSCs based cellular therapy for MI . Thus, many signaling pathways have been suggested to participate in autophagy regulation. As the main problem of stem cell therapy is that the survival ability of implanted stem cells is poor, the survival mechanism and related regulation are more and more concerned by people. Until now, there are some potential signal transduction pathways such as PI3K/Akt/nuclear factor-kappa B, MEK/ERK and SCF/c-kit which participate in the relationship between autophagy and apoptosis has been reported to participate in autophagy [48,52,53]. Besides, autophagy plays a key role in promoting the survival of transplanted stem cells in MI and it may provide a new therapeutic approach for stem cell therapy and regenerative medicine .
Remained problems and future directions
In recent years, studies of BM-MSCs have been made great progresses, but there are still some problems to be solved. Firstly, no standard method has been putted forward about isolation, purification and specific marker molecules for the identification of BM-MSCs.Secondly, the efficiency of BM-MSCs differentiation is not ideal, which is currently one of the research focus on how to induce BM-MSCs to differentiate to the single specific tissue and cells [5,55-58]. Thirdly, the signal transduction mechanism and the molecular basis of BM-MSCs’ differentiation such as which transcription factors or gene were activated to make it for some specific differentiation is still not clear though it is generally considered to be related to reprogramming of BM-MSCs. Fourthly, whether the induced cells have real structure and function, homing to the corresponding organization are need to be further investigated. Lastly, although there is no report on the transformation of BM-MSCs into malignant cells and the production of abnormal extracellular matrix, the safety of BM-MSCs is also worth noting.
On the other hand, BM-MSCs have important clinical application value in cell replacement therapy, gene therapy and tissue regeneration. Bone marrow collection is also convenient, safe and cause less injury, especially has no obvious complications to the donor. Therefore BMMSCs is conducive to the expansion and autologous transplantation in vitro , thereby becoming the promising source of tissue engineering. BM-MSCs were amplified in vitro , which can directly carry on cell transplantation or implant biomaterials, and then transplanted into the body to repair tissue defects. In addition, retroviral vector, adenovirus vector which carry the target gene can be also successfully transfected into BM-MSCs, and have high expression in vivo . Besides, BM-MSCs are relatively primitive cells, whose immunogenicity is weak and can inhibit the mixed lymphocyte reaction. However, previous studies also reported the clinical application of BM-MSCs are not matched with donor, host immune rejection or graft versus host reaction [59-61]. Moreover, allogeneic bone marrow transplantation of mesenchymal stem cells in severe idiopathic aplastic anemia patients have also been shown to improve the effect of bone marrow stromal function [62,63]. Allogeneic transplantation of BM-MSCs not only has ability of multidirectional differentiation, but also has special immune tolerance, allowing them to survive in allogeneic environment, in which provides a possibility for the application of BM-MSCs MI therapy.
This work was supported by National Nature Science Foundation of China (No. 81400274, No. 81500202 No.31440039).
Conflict of interest
We declare that we have no conflict of interest
- Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:29-20.
- Liu Y, Zhang X, Dai Y, Shu C, Qu P, et al. (2008) Effects of bone marrow mesenchymal stem cells on learning and memory functional recovery in neonatal rats with hypoxic-ischemic brain damage. Zhonghua Er KeZaZhi 46:648-653.
- Togha M, Jahanshahi M, Alizadeh L, Jahromi SR, Vakilzadeh G, et al. (2016) Rapamycin augments immunomodulatory properties of bone marrow-Derived mesenchymal stem cells in experimental autoimmune encephalomyelitis. Mol Neurobiol 54: 2445-2457.
- Ahmed K, Jeong GH, Chakraborty R, Ahmed S, Hong YJ, et al. (2014) Comparison of zotarolimus- and everolimus-eluting stents in patients with ST-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. J Cardiol 64:273-278.
- Al-Hezaimi K, Ramalingam S, Al-Askar M, ArRejaie AS, Nooh N, et al. (2016) Real-time-guided bone regeneration around standardized critical size calvarial defects using bone marrow-derived mesenchymal stem cells and collagen membrane with and without using tricalcium phosphate: An in vivo micro-computed tomographic and histologic experiment in rats. Int J Oral Sci 8:7-15.
- Amiri F, Molaei S, Bahadori M, Nasiri F, Deyhim MR, et al. (2016) Autophagy-modulated human bone marrow-derived mesenchymal stem cells accelerate liver restoration in mouse models of acute liver failure. Iran Biomed J 20:135-144.
- An X, Ma K, Zhang Z, Zhao T, Zhang X, et al. (2016) miR-17, miR-21, and miR-143 enhance adipogenic differentiation from porcine bone marrow-derived mesenchymal stem cells. DNA Cell Biol 35:410.
- Atabek ME (2013) Reliability and validity of homeostasis model assessment for insulin resistance and beta-cell dysfunction in critically ill children with hyperglycemia. J Pediatr Endocrinol Metab 26:1215.
- Nakano M, Nagaishi K, Konari N, Saito Y, Chikenji T, et al. (2016) Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci Rep 6:24805.
- Ren G, Chen X, Dong F, Li W, Ren X, et al. (2012) Concise review: Mesenchymal stem cells and translational medicine: Emerging issues. Stem Cells Transl Med 1:51-58.
- Hao L, Hailun Z, Qi W, Wei L (2015) Changes in bone marrow mesenchymal stem cells osteogenesis by the regulation of Lnk/stem cell factor-cKit signaling. Hua Xi Kou Qiang Yi XueZaZhi 33:633-637.
- Luo F, Liu T, Wang J, Li J, Ma P, et al. (2016) Bone marrow mesenchymal stem cells participate in prostate carcinogenesis and promote growth of prostate cancer by cell fusion in vivo. Oncotarget 7(21):30924-30934.
- Xiao WZ, Gu XC, Hu B, Liu XW, Zi Y et al. (2016) Role of microRNA-129-5p in osteoblast differentiation from bone marrow mesenchymal stem cells. Cell Mol Biol (Noisy-le-grand) 62:95-99.
- Zheng S, Yang J, Tang Y, Shao Q, Guo L, et al. (2015) Effect of bone marrow mesenchymal stem cells transplantation on the serum and liver HMGB1 expression in rats with acute liver failure. Int J Clin Exp Pathol 8:15985-15992.
- Deb A, Wang S, Skelding KA, Miller D, Simper D, et al. (2003) Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients. Circulation 107:1247-1249.
- Bader AM, Klose K, Bieback K, Korinth D, Schneider M, et al. (2015) Hypoxic Preconditioning Increases Survival and Pro-Angiogenic Capacity of Human Cord Blood Mesenchymal Stromal Cells In Vitro. PLoS One 10:e0138477.
- Bakshi AA, JS Bavikar, SB Asegaonkar, JS Bardapurkar, V Domple, et al. (2014) Evaluation of usefulness of serum insulin as sensitive predictor of cardiovascular dysfunction in obese individuals with normal lipid profile. J Clin Diagn Res 8:CC10-12.
- Barazzoni R, Zanetti M, GortanCappellari G, Semolic A, Boschelle M, et al. (2012) Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-kappaB inhibitor (IkappaB)-nuclear factor-kappaB (NFkappaB) activation in rat muscle, in the absence of mitochondrial dysfunction. Diabetologia 55:773-782.
- Abe Y, Watanabe T (2014) Renal tubular dysfunction in patients with molecular defects of the insulin receptor gene. Eur J Pediatr 173:263.
- Kotobuki N, Hirose M, Takakura Y, Ohgushi H (2004) Cultured autologous human cells for hard tissue regeneration: Preparation and characterization of mesenchymal stem cells from bone marrow. Artif Organs 28:33-39.
- Hou L, Dong Q, Wu YJ, Sun YX, Guo YY, et al. (2016) Gonadotropins facilitate potential differentiation of human bone marrow mesenchymal stem cells into Leydig cells in vitro. Kaohsiung J Med Sci 32:1-9.
- Ock SA, Subbarao RB, Lee YM, Lee JH, Jeon RH, et al. (2016) Comparison of immunomodulation properties of porcine mesenchymal stromal/stem cells derived from the bone marrow, adipose tissue, and dermal skin tissue. Stem Cells Int 2016:9581350.
- Wang H, Jing C, Tan X, Luo J, Liu C, et al. (2015) An experimental study on segmental defects reconstruction of canine mandible with allogenic bone marrow mesenchymal stem cells combined with lyophilized bone. Zhonghua Kou Qiang Yi XueZaZhi 50:720-724.
- Zhang F, Zhang Z, Sun D, Dong S, Xu J, et al. (2016) Periostin: A downstream mediator of ephb4-induced osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. Stem Cells Int 2016:241829.
- Zhu N, Wang H, Wang B, Wei J, Shan W, et al. (2016) A member of the nuclear receptor superfamily, designated as NR2F2, supports the self-renewal capacity and pluripotency of human bone marrow-derived mesenchymal stem cells. Stem Cells Int 2016:5687589.
- AlzebdehDA, Matthew HW (2017) metabolic oscillations in co-cultures of hepatocytes and mesenchymal stem cells: Effects of seeding arrangement and culture mixing. J Cell Biochem [Epub ahead of print].
- Lee HJ, Oh SH, HW Jang, JH Kwon, KJ Lee, et al. (2016) Long-term effects of bone marrow-derived mesenchymal stem cells in dextran sulfate sodium-induced murine chronic colitis. Gut Liver 10:412-419.
- Shangguan L, Li X, Wang Z, Luo Z (2015) Transforming growth factor-beta1 induces bone marrow-derived mesenchymal stem cells to differentiate into cancer-associated fibroblasts. Zhonghua Zhong Liu ZaZhi 37:804-809.
- Sun Q, Yang Y, Li X, He B, Jia Y, et al. (2016) Folate deprivation modulates the expression of autophagy- and circadian-related genes in HT-22 hippocampal neuroncells through GR-mediated pathway. Steroids 112:12.
- Walter C, Clemens LE, Muller AJ, Fallier-Becker P, Proikas-Cezanne T, et al. (2016) Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro. Neuropharmacology 108:24-38.
- Li F, Zheng X, Liu Y, Li P, Liu X, et al. (2016) Different roles of CHOP and JNK in mediating radiation-induced autophagy and apoptosis in breast Cancer cells. Radiat Res 185:539.
- Sano O, Kazetani K, Funata M, Fukuda Y, Matsui J, et al. (2016) Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition. FEBS Lett 590: 1576-1585.
- Chen K, Li J, Li S, Feng J, Wu L, et al. (2016) 15d-PGJ2 alleviates ConA-induced acute liver injury in mice by up-regulating HO-1 and reducing hepatic cell autophagy. Biomed Pharmacother 80:183-192.
- Kesidou E, Lagoudaki R, Touloumi O, Poulatsidou KN, Simeonidou C (2013) Autophagy and neurodegenerative disorders. Neural Regen Res 8:2275-2283.
- Liu B, Cao Y, Jiang H, Mao A (2013) Autophagy facilitates the sorafenib resistance of hepatocellular carcinoma cells. West Indian Med J 62:698-700.
- Huang H, Li X, Zhuang Y, Li N, Zhu X, et al. (2014) Class A scavenger receptor activation inhibits endoplasmic reticulum stress-induced autophagy in macrophage. J Biomed Res 28:213-221.
- Ahmed K, Jeong MH, Chakraborty R, Ahmed S, Hong YJ, et al. (2012) Coronary stents in patients with st-elevation myocardial infarction and chronic kidney disease undergoing primary percutaneous coronary intervention. Korean Circ J 42:830-838.
- Di Michele S, Mirabelli F, Galzerano D, Mankad S (2014) An unusual myocardial infarction. Echo Res Pract 1:K9-K12.
- Kalantari Meibodi M (2014) Door to electrocardiography (ECG) and needle times in patients with myocardial infarction. Emerg (Tehran) 2:150.
- Bashar T, Akhter N (2014) Study on oxidative stress and antioxidant level in patients of acute myocardial infarction before and after regular treatment. Bangladesh Med Res Counc Bull 40:79-84.
- Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, et al. (2005) Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 112:1128-1135.
- Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, et al. (2010) Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 107:913-922.
- Cruz FF, Rocco PR (2015) Hypoxic preconditioning enhances mesenchymal stromal cell lung repair capacity. Stem Cell Res Ther 6:130.
- Qin HH, Filippi C, Sun S, Lehec S, Dhawan A, et al. (2015) Hypoxic preconditioning potentiates the trophic effects of mesenchymal stem cells on co-cultured human primary hepatocytes. Stem Cell Res Ther 6:237.
- Rosova I, Dao M, Capoccia B, Link D, Nolta JA (2008) Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells 26:2173-2182
- Volkmer E, Kallukalam BC, Maertz J, Otto S, Drosse I, et al. (2010) Hypoxic preconditioning of human mesenchymal stem cells overcomes hypoxia-induced inhibition of osteogenic differentiation. Tissue Eng Part A 16:153-164.
- Kaarniranta K, Kauppinen A, Blasiak J, Salminen A (2012) Autophagy regulating kinases as potential therapeutic targets for age-related macular degeneration. Future Med Chem 4:2153-2161.
- Li D, Yan T, Xu Z, Jia J, Zheng Z, et al. (2016) Spironolactone promotes autophagy via inhibiting PI3K/AKT/mTOR pathway and reduce adhesive damage in podocytes under mechanical stress. Biosci Rep 36: e00355.
- Li L, Zhang Q, Tan J, Fang Y, An X, et al. (2014) Autophagy and hippocampal neuronal injury. Sleep Breath 18:243-249.
- Zhang Z, Yang M, Wang Y, Wang L, Jin Z, et al. (2016) Autophagy regulates the apoptosis of bone marrow-derived mesenchymal stem cells under hypoxic condition via AMP-activated protein kinase/mammalian target of rapamycin pathway.Cell Biol Int 40:671.
- Liu J, Hao H, Huang H, Tong C, Ti D, et al. (2015) Hypoxia regulates the therapeutic potential of mesenchymal stem cells through enhanced autophagy. Int J Low Extrem Wounds 14:63-72.
- Gu J, Hu W, Song ZP, Chen YG, Zhang DD et al. (2016) Rapamycin Inhibits Cardiac Hypertrophy by Promoting Autophagy via the MEK/ERK/Beclin-1 Pathway. Front Physiol 7:104.
- Lee Y, Jung J, Cho KJ, Lee SK, Park JW et al. (2013) Increased SCF/c-kit by hypoxia promotes autophagy of human placental chorionic plate-derived mesenchymal stem cells via regulating the phosphorylation of mTOR. J Cell Biochem 114:79-88.
- Mo Y, Tang L, Ma Y, Wu S (2016) Pramipexole pretreatment attenuates myocardial ischemia/reperfusion injury through upregulation of autophagy. Biochem Biophys Res Commun 473:1119-1124.
- Bandara N, Gurusinghe S, Chen H, Chen S, Wang LX, et al. (2016) Minicircle DNA-mediated endothelial nitric oxide synthase gene transfer enhances angiogenic responses of bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 7:48.
- Barlow AD, Thomas DC (2015) Autophagy in diabetes: beta-cell dysfunction, insulin resistance, and complications. DNA Cell Biol 34:252-260.
- Barlow J, Jensen VH, Jastroch M, Affourtit C (2016) Palmitate-induced impairment of glucose-stimulated insulin secretion precedes mitochondrial dysfunction in mouse pancreatic islets. Biochem J 473:487-496.
- Bertolo A, Mehr M, Janner-Jametti T, Graumann U, Aebli N, et al. (2016) An in vitro expansion score for tissue-engineering applications with human bone marrow-derived mesenchymal stem cells. J Tissue Eng Regen Med 10:149-161.
- Ferris DJ, Frisbie DD, Kisiday JD, McIlwraith CW, Hague BA, et al. (2014) Clinical outcome after intra-articular administration of bone marrow derived mesenchymal stem cells in 33 horses with stifle injury. Vet Surg 43:255-265.
- Wong KL, Lee KB, Tai BC, Law P, Lee EH, et al. (2013) Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up. Arthroscopy 29:2020-2028.
- Sohn HS, Heo JS, Kim HS, Choi Y, Kim HO (2013) Duration of in vitro storage affects the key stem cell features of human bone marrow-derived mesenchymal stromal cells for clinical transplantation. Cytotherapy 15:460-466.
- Cle DV, Santana-Lemos B, Tellechea MF, Prata KL, Orellana MD, et al. (2015) Intravenous infusion of allogeneic mesenchymal stromal cells in refractory or relapsed aplastic anemia. Cytotherapy 17:1696-1705.
- Jiang S, Xia M, Yang J, Shao J, Liao X, et al. (2015) Novel insights into a treatment for aplastic anemia based on the advanced proliferation of bone marrowderived mesenchymal stem cells induced by fibroblast growth factor 1. Mol Med Rep 12:7877-7882.