• Users Online: 172
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 1-5

Mesenchymal stem cell therapy for diabetic foot ulcer


1 The Key Tissue Engineering of Jilin Province, Siping Hospital of China Medical University, Siping, Jilin, China
2 Department of Vascular Surgery, Xuanwu Hospital of the Capital Medical University, Beijing, China

Date of Web Publication10-Jul-2018

Correspondence Address:
Yongquan Gu
Department of Vascular Surgery, Xuanwu Hospital of the Capital Medical University, Beijing 100053
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_1_18

Rights and Permissions
  Abstract 

Diabetic foot (DF) disease continues to be a major cause of mortality and disability. The pathophysiology of DF is multifactorial and includes neuropathy, infection, ischemia, and abnormal foot structure and biomechanics. Current therapies are limited; however, based on recent research efforts, there is rising hope for promising and more effective stem cell therapeutic approaches for these patients. In this review, we discuss mesenchymal stem cells as tools for cell/scaffold-based therapies for nonhealing wounds. We have reviewed the main clinical trials dividing them based on their clinical applications and taken into account the ethical issue associated with the stem cell therapy.

Keywords: Critical limb ischemia, diabetic foot, mesenchymal stem cells


How to cite this article:
Liu Y, Gu Y. Mesenchymal stem cell therapy for diabetic foot ulcer. Vasc Invest Ther 2018;1:1-5

How to cite this URL:
Liu Y, Gu Y. Mesenchymal stem cell therapy for diabetic foot ulcer. Vasc Invest Ther [serial online] 2018 [cited 2018 Dec 18];1:1-5. Available from: http://www.vitonline.org/text.asp?2018/1/1/1/236291


  Introduction Top


Diabetic foot ulcer (DFU) is a common complication and the main cause of amputation of diabetes mellitus (DM). According to epidemiological studies, approximately 15% of diabetic patients experience DFUs during their lifetime. Thus, the probability of these patients requiring an amputation is 40 times the rate in nondiabetic patients, and the total financial burden associated with this condition is very high.[1],[2] Neuropathy, peripheral vascular disease, and reduced resistance to infection are the recognized risk factors leading to the development of DFUs, which have all the characteristics of a chronic wound.[3],[4] As diabetes has shown a growing trend and becomes a global public health threat over the past two decades,[5],[6] DFU is becoming a worldwide threat to public health. Traditional therapies, including local wound care, treatment for infection, and ischemia, do not change the fundamental pathology underlying DFU, and their therapeutic effects are limited.

Over the last two decades, cell therapy had shown great promise for the treatment of a lot of clinical diseases, which was conceived as an innovative way to improve pathophysiological condition and the prognosis of DFU. Even a variety type of stem and progenitor cells have been evaluated, mesenchymal stem cells (MSCs) were considered as the best therapeutic potential cells, owing to their greater ease of isolation and capacity for proliferation and differentiation in vivo and in vitro. Here, we focus on the current status of research into MSCs as a stem cell-based therapy for DFU and the unique challenges to their successful application toward a standard clinical therapy.

Pathophysiology of diabetic foot ulcer

Three underlying major pathologies, mutually interacting for the DFU, are as follows: ischemia, neuropathy, and infection.[7],[8],[9],[10]

Neuropathy

Neuropathy is the most common etiology underlying DFU, with a prevalence ranging >60%.[11] About 10%–18% of patients appear to be already affected by peripheral neuropathy at the time of DM diagnosis,[12] and distal sensorimotor polyneuropathy is usually present in about 42% of diabetic patients after 20 years.[13] The distal neuropathy of diabetes frequently involves sensory, motor, and autonomic, each of which contributes to foot ulcer development. There are several hypotheses that are thought to responsible for these abnormalities, which include deficiencies in sorbitol metabolism via the polyol pathway resulting from chronic hyperglycemia.[14],[15] The loss of protective sensation in the neuropathic patient lets foot wounds go undetected in tissue breakdown and ulceration.

Motor nerve involvement

Motor neuropathy is related to the damage of demyelination and motor endplate. The distal motor nerves are most commonly affected, which led to small intrinsic muscles atrophy of the foot, and produce an imbalance of the long flexor and extensor tendons. This pathological phenomenon is mainly related to two abnormalities. First, it results in collapse of the arch and induces the classic high-arched foot and claw toe deformity.[16],[17] Thus, pressures are gradually abnormally distributed on the plantar aspect of the foot, and some plantar sites become prone to ulceration under high pressures.[18],[19],[20],[21],[22] Second, loss of stability of the metatarsophalangeal joints during midstance of the gait is observed. The distal metatarsal fat pads displaces resulting in hyperextension of the toes and the natural cushioning of the metatarsal heads reducing. These abnormal changes that increase plantar pressures led to callus formation and potential skin breakdown. Due to loss of internal muscles and the disruption of the normal bony relationships of the distal foot, eventually leading to a wider and thicker foot than normal. Furthermore, the primary shoes do not fit any longer, which in turn cause areas of local trauma. Anyway, overcompensation by extrinsic muscles can lead to musculoskeletal deformities.[23]

Autonomic involvement

Autonomic neuropathy changes are manifested as reduced sweating at the epidermal level and arteriovenous shunting at the subcutaneous and dermal level. Hypohidrosis leads to dry skin and callus formation. Arteriovenous shunting reduced the delivery of nutrients and oxygen to the tissues led them susceptible to break down.[24] Furthermore, distal arterial flow and pressure are increased due to the loss of peripheral sympathetic vascular tone in the lower limb, which might contribute to peripheral edema by damaging the capillary basement membrane.[25] Increased edema might be another element of minor trauma caused by wearing shoes that not fit anymore. Skin cracks may become gateways to bacterial invasion and increase the likelihood of infection.[26]

Sensory neuropathy

The effects of motor and autonomic neural abnormalities are much less than the loss of sensory neural function on foot protection. When these fibers are affected, protective sensation is lost which manifests as a distal, symmetric loss of sensation described as a “glove and stocking” distribution.[27] In this condition, patients are unable to detect increased loads, repeated trauma, pain from shearing forces, or injuries such as fractures, ulceration, and foot deformities. This sequence of events allows patients walk with a false sense of security and repeated trauma to the foot.[28],[29]


  Etiology of Diabetic Foot Ulceration Top


Ischemia

The other major underlying cause of DFU is peripheral vascular disease.[17] Purely ischemic DFUs are uncommon, representing only 10%–20% of ulcers in diabetic patients, and another 15%–33% have a mixed neuropathic-vascular etiology.[30],[31] Overall, the incidence of peripheral arterial disease (PAD) is estimated to be 2–4 times more common in diabetic patients than in others.[31]

PAD in diabetic patients often occurs in numerous vessels, especially in anterior tibial, posterior tibial, and peroneal arteries.[9],[10],[32],[33] Its hallmark occurs in the tibioperoneal vessels while relative sparing of the pedal vessels. Characteristically, occlusive lesions that spare the arteries are usually above the knee in diabetic patients, while the calcific infrapopliteal arteries in single- or multiple-level disease. One or more of the large vessels at the ankle and in the foot are spared. Basically, the peroneal artery in the calf is the last one to occlude [Review in 31]. Thus, it has the potential to provide good blood flow via its terminal tributary to a single tibial artery, peroneal artery, or a pedal bypass to the foot.

Of note, in DFU, microangiopathy induces capillary basement membrane thickening, reducing the supply of oxygen and nutrients, and microcirculating ischemia. Lack of perfusion reduces tissue elasticity, leads to rapid tissue death, and delays wound healing.[34] Once an ulcer is formed, microangiopathy might aggravate chronic ulcer development.

Finally, autonomic neural abnormalities reduce the normal vasoconstriction in the lower leg arteries withstanding, which led to an increase in the intraluminal flow and pressure.[35] Reduced vasoconstrictive ability in turn reduces vessels' capacity to respond to systolic blood pressure expansion. The association of high flow and reduced wall motion promotes the formation of plaque in calf arteries.[36]

Infection

It is reported that 40%–80% of DFU has evidence of infection. Several factors increase the risk of development of DFU, including diabetic neuropathy, peripheral arterial disease, and immunologic impairment, especially of the peripheral neuropathy effect.[37] As described above, due to loss of neural protection, diabetic patients are prone to occur repeated trauma and ulcer.

Diabetic-related infection has two characteristics. First, the host immune function is impaired, which is manifested in the function of defects in leukocyte function with serum glucose levels ≥150 ml/dl.[38] The capability of leukocyte is decreased in migration and phagocytosis, intracellular activity is related to hyperglycemia, and impaired cellular immune response is neither spared.[39],[40] These abnormal changes cause a prolonged inflammatory state, a catabolic state in an open wound, gluconeogenesis from protein breakdown. This metabolic dysfunction further impairs the synthesis of proteins, fibroblasts, and collagen at the lesion. Infection is poorly tolerated in diabetic patients and aggravates blood glucose control, which further affects the host's response to infection. Second, the types of bacteria infected with DFU are different in contrast to nondiabetic individuals. An average of five to eight different organisms [41],[42],[43],[44] is related to diabetic-related infection, which causes complex infections of DFU. The most prevalent organisms identified were Staphylococcus aureus, coagulase-negative Staphylococcus, group B Streptococcus, Proteus,  Escherichia More Details coli, Pseudomonas, and Bacteroides. Methicillin-resistant S. aureus (MRSA) is the major infected source in DFUs and prolonged time to healing.[41],[43],[44],[45]

DF infection can be classified into two kinds. One is often mild infections associated with a superficial ulcer, <2 cm of surrounding cellulitis, and no signs of systemic toxicity. In this lesion, the most notable organisms are aerobic Gram-positive cocci, such as S. aureus, coagulase-negative S. aureus, and streptococci. The other one is more severe; the lesion is usually >2 cm of surrounding cellulitis, deeper ulceration, or an undrained abscess, gangrene, or necrotizing fasciitis, which is life- or limb-threatening, and commonly caused by MRSA infection.[41],[46],[47]

Mesenchymal stem cells

MSCs were first found in bone marrow in 1966,[48] which are isolated later from various other tissue types, including bone marrow, umbilical cord blood, adipose tissue, and amniotic membrane. It has been recommended that MSCs must fulfill the following cell surface marker expression criteria: ≥95% of the population must express CD105, CD73, and CD90, and ≤2% of the population must not express CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA class II MSCs must be able to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro.[49]

Recent studies reported that MSCs have the capability of multidirectional differentiation and weak immunogenicity. As MSCs are easy collected, these cells are widely used in the field of regenerative medicine research.

Mesenchymal stem cells in diabetic foot ulcer tissue repair

MSCs are believed to have an important role in tissue repair.[50] MSCs can recruit and differentiate at the lesion after intravenous and local injection. MSCs could affect tissue healing and regeneration through many different routes. One of the most intriguing properties is the capability of ex vivo differentiation. A greating study suggests that MSCs can migrate toward injured sites in response to inflammation and differentiate into multiple cells to repair damaged tissues.[51] Sasaki et al. revealed that MSCs can differentiate into a variety of skin cell types,[52] and Wu et al. reported that MSCs enhance wound healing not only through differentiation but also angiogenesis.[53] Several studies revealed that MSCs could differentiate into endothelial cells in anti-angiogenic environments.[54] Furthermore, a subpopulation of MSCs, which participates to stabilize vessel walls and promote vessel maturation during angiogenesis, known as pericytes,[55] has been proved to be derived from bone marrow following injury.[56] Thus, MSCs have the potential to support new vessel growth in a DFU and to overcome the critical aspect of barriers to current therapies.

The other intriguing role in MSCs is secreting trophic factors to influence the microenvironment in the wound bed. Stimulated by hypoxia and local inflammation, MSCs can release many factors at the wound margin to support epidermal cells proliferate and new blood capillaries grow, such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-β, insulin growth factor-1, and angiopoietin-1.[57],[58],[59],[60] Furthermore, MSCs stimulate endothelial cell recruitment through the secretion of vascular endothelial growth factor, modulate scar formation through prostaglandin E2 secretion, regulate interleukin (IL-10), IL-6, and IL-8, and reduce of collagen production.[61],[62],[63] Taken together, MSCs participate in the whole process and promotes tissue regeneration and repair.

Mesenchymal stem cells as immune modulators

Finally, MSCs have immunomodulatory properties through the production of soluble factors.[53],[64],[65],[66],[67] MSCs can regulate IL-10 production to alter the activity of dendritic cells. MSCs can inhibit T-cell production, such as CD4+ and CD+ 8 T-cells, and increase the number of CD4+CD25+FoxP3+ T-regulatory cells to suppress the immune response.[68],[69] MSCs can inhibit B-cells and NK cells proliferation and IgG secretion of B-cells.[70] Based on these characteristics and their potential immunoprivileged status, MSC therapy represents a method to treat conditions that currently result in generally poor outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
American Diabetes Association. Economic costs of diabetes in the U.S. In 2007. Diabetes Care 2008;31:596-615.  Back to cited text no. 1
    
2.
Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet 2005;366:1719-24.  Back to cited text no. 2
[PUBMED]    
3.
Dinh TL, Veves A. A review of the mechanisms implicated in the pathogenesis of the diabetic foot. Int J Low Extrem Wounds 2005;4:154-9.  Back to cited text no. 3
[PUBMED]    
4.
American Diabetes Association. Consensus development conference on diabetic foot wound care: 7-8 April 1999, Boston, Massachusetts. American diabetes association. Diabetes Care 1999;22:1354-60.  Back to cited text no. 4
    
5.
Shahbazian H, Yazdanpanah L, Latifi SM. Risk assessment of patients with diabetes for foot ulcers according to risk classification consensus of international working group on diabetic foot (IWGDF). Pak J Med Sci 2013;29:730-4.  Back to cited text no. 5
    
6.
Ramachandran A, Snehalatha C, Shetty AS, Nanditha A. Trends in prevalence of diabetes in Asian countries. World J Diabetes 2012;3:110-7.  Back to cited text no. 6
    
7.
Connor H. Some historical aspects of diabetic foot disease. Diabetes Metab Res Rev 2008;24 Suppl 1:S7-S13.  Back to cited text no. 7
    
8.
Boulton AJ. The diabetic foot: Grand overview, epidemiology and pathogenesis. Diabetes Metab Res Rev 2008;24 Suppl 1:S3-6.  Back to cited text no. 8
    
9.
Papanas N, Maltezos E, Edmonds M. St. Vincent declaration after 15 years or who cleft the devil's foot? Vasa 2006;35:3-4.  Back to cited text no. 9
    
10.
Edmonds ME. The diabetic foot, 2003. Diabetes Metab Res Rev 2004;20 Suppl 1:S9-S12.  Back to cited text no. 10
    
11.
Grunfeld C. Diabetic foot ulcers: Etiology, treatment, and prevention. Adv Intern Med 1992;37:103-32.  Back to cited text no. 11
    
12.
Lehtinen JM, Niskanen L, Hyvönen K, Siitonen O, Uusitupa M. Nerve function and its determinants in patients with newly-diagnosed type 2 (non-insulin-dependent) diabetes mellitus and in control subjects – A 5-year follow-up. Diabetologia 1993;36:68-72.  Back to cited text no. 12
    
13.
O'Brien IA, Corrall RJ. Epidemiology of diabetes and its complications. N Engl J Med 1988;318:1619-20.  Back to cited text no. 13
    
14.
Laing P. The development and complications of diabetic foot ulcers. Am J Surg 1998;176:11S-19S.  Back to cited text no. 14
    
15.
Kamal K, Powell RJ, Sumpio BE. The pathobiology of diabetes mellitus: Implications for surgeons. J Am Coll Surg 1996;183:271-89.  Back to cited text no. 15
    
16.
Borssén B, Bergenheim T, Lithner F. The epidemiology of foot lesions in diabetic patients aged 15-50 years. Diabet Med 1990;7:438-44.  Back to cited text no. 16
    
17.
Bowering CK. Diabetic foot ulcers. Pathophysiology, assessment, and therapy. Can Fam Physician 2001;47:1007-16.  Back to cited text no. 17
    
18.
Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg 2006;45:S1-66.  Back to cited text no. 18
    
19.
Boulton AJ, Kirsner RS, Vileikyte L. Clinical practice. Neuropathic diabetic foot ulcers. N Engl J Med 2004;351:48-55.  Back to cited text no. 19
    
20.
Edmonds ME, Foster AV, Sanders LJ. Stage 3: The ulcerated foot. In: A Practical Manual of Diabetic Footcare. Oxford: Blackwell; 2004. p. 62-101.  Back to cited text no. 20
    
21.
Veves A, Manes C, Murray HJ, Young MJ, Boulton AJ. Painful neuropathy and foot ulceration in diabetic patients. Diabetes Care 1993;16:1187-9.  Back to cited text no. 21
    
22.
Papanas N, Maltezos E. The diabetic foot: Established and emerging treatments. Acta Clin Belg 2007;62:230-8.  Back to cited text no. 22
    
23.
Morag E, Pammer S, Boulton A, Young M, Deffner K, Cavanagh P, et al. Structural and functional aspects of the diabetic foot. Clin Biomech (Bristol, Avon) 1997;12:S9-S10.  Back to cited text no. 23
    
24.
Saltzman CL, Pedowitz WJ. Diabetic foot infections. Instr Course Lect 1999;48:317-20.  Back to cited text no. 24
    
25.
Katz MA, McCuskey P, Beggs JL, Johnson PC, Gaines JA. Relationships between microvascular function and capillary structure in diabetic and nondiabetic human skin. Diabetes 1989;38:1245-50.  Back to cited text no. 25
    
26.
Tentolouris N, Marinou K, Kokotis P, Karanti A, Diakoumopoulou E, Katsilambros N, et al. Sudomotor dysfunction is associated with foot ulceration in diabetes. Diabet Med 2009;26:302-5.  Back to cited text no. 26
    
27.
Levin ME. Diabetes and peripheral neuropathy. Diabetes Care 1998;21:1.  Back to cited text no. 27
    
28.
Boulton AJ, Hardisty CA, Betts RP, Franks CI, Worth RC, Ward JD, et al. Dynamic foot pressure and other studies as diagnostic and management aids in diabetic neuropathy. Diabetes Care 1983;6:26-33.  Back to cited text no. 28
    
29.
Fernando DJ, Masson EA, Veves A, Boulton AJ. Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration. Diabetes Care 1991;14:8-11.  Back to cited text no. 29
    
30.
Sumpio BE. Contemporary evaluation and management of the diabetic foot. Scientifica (Cairo) 2012;2012:435487.  Back to cited text no. 30
    
31.
Weiss JS, Sumpio BE. Review of prevalence and outcome of vascular disease in patients with diabetes mellitus European. J Vasc Endovasc Surg 2006;31:143-50.  Back to cited text no. 31
    
32.
International Diabetes Federation and International Working Group of the Diabetic Foot. In: Bakker K, Foster AV, van Houtoum WH, Riley P, editors. Time to Act. Netherlands; 2005.  Back to cited text no. 32
    
33.
Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients: A comparison of severity and outcome. Diabetes Care 2001;24:1433-7.  Back to cited text no. 33
    
34.
O'Brien IA, Corrall RJ, Krolewski AS. Epidemiology of diabetes and its complications, New England. J Med 1988;318:1619-20.  Back to cited text no. 34
    
35.
Rayman G, Hassan A, Tooke JE. Blood flow in the skin of the foot related to posture in diabetes mellitus. Br Med J (Clin Res Ed) 1986;292:87-90.  Back to cited text no. 35
    
36.
McMillan DE. Blood flow and the localization of atherosclerotic plaques. Stroke 1985;16:582-7.  Back to cited text no. 36
    
37.
Reiber GE, Vileikyte L, Boyko EJ, del Aguila M, Smith DG, Lavery LA, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999;22:157-62.  Back to cited text no. 37
    
38.
Inzucchi SE. Clinical practice. Management of hyperglycemia in the hospital setting. N Engl J Med 2006;355:1903-11.  Back to cited text no. 38
    
39.
Bagdade JD, Root RK, Bulger RJ. Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes 1974;23:9-15.  Back to cited text no. 39
    
40.
Hobizal KB, Wukich DK. Diabetic foot infections: Current concept review. Diabet Foot Ankle 2012;3.  Back to cited text no. 40
    
41.
Lipsky BA, Tabak YP, Johannes RS, Vo L, Hyde L, Weigelt JA, et al. Skin and soft tissue infections in hospitalised patients with diabetes: Culture isolates and risk factors associated with mortality, length of stay and cost. Diabetologia 2010;53:914-23.  Back to cited text no. 41
    
42.
Blume PA, Paragas LK, Sumpio BE, Attinger CE. Single-stage surgical treatment of noninfected diabetic foot ulcers. Plast Reconstr Surg 2002;109:601-9.  Back to cited text no. 42
    
43.
Citron DM, Goldstein EJ, Merriam CV, Lipsky BA, Abramson MA. Bacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agents. J Clin Microbiol 2007;45:2819-28.  Back to cited text no. 43
    
44.
Nelson EA, O'Meara S, Golder S, Dalton J, Craig D, Iglesias C, et al. Systematic review of antimicrobial treatments for diabetic foot ulcers. Diabet Med 2006;23:348-59.  Back to cited text no. 44
    
45.
Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med 1999;341:1906-12.  Back to cited text no. 45
    
46.
Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39:885-910.  Back to cited text no. 46
    
47.
Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): Prospective, randomised, controlled, double-blinded, multicentre trial. Lancet 2005;366:1695-703.  Back to cited text no. 47
    
48.
Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 1966;16:381-90.  Back to cited text no. 48
    
49.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 2006;8:315-7.  Back to cited text no. 49
    
50.
Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: A new strategy for immunosuppression and tissue repair. Caell Res 2010;20:510-8.  Back to cited text no. 50
    
51.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7.  Back to cited text no. 51
    
52.
Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D, Shimizu H, et al. Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 2008;180:2581-7.  Back to cited text no. 52
    
53.
Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 2007;25:2648-59.  Back to cited text no. 53
    
54.
Janeczek Portalska K, Leferink A, Groen N, Fernandes H, Moroni L, van Blitterswijk C, et al. Endothelial differentiation of mesenchymal stromal cells. PLoS One 2012;7:e46842.  Back to cited text no. 54
    
55.
Blocki A, Wang Y, Koch M, Peh P, Beyer S, Law P, et al. Not all MSCs can act as pericytes: Functional in vitro assays to distinguish pericytes from other mesenchymal stem cells in angiogenesis. Stem Cells Dev 2013;22:2347-55.  Back to cited text no. 55
    
56.
Kokovay E, Li L, Cunningham LA. Angiogenic recruitment of pericytes from bone marrow after stroke. J Cereb Blood Flow Metab 2006;26:545-55.  Back to cited text no. 56
    
57.
Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G, et al. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 2012;33:136-43.  Back to cited text no. 57
    
58.
Ma XL, Liu KD, Li FC, Jiang XM, Jiang L, Li HL, et al. Human mesenchymal stem cells increases expression of α-tubulin and angiopoietin 1 and 2 in focal cerebral ischemia and reperfusion. Curr Neurovasc Res 2013;10:103-11.  Back to cited text no. 58
    
59.
Aguilar S, Scotton CJ, McNulty K, Nye E, Stamp G, Laurent G, et al. Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis. PLoS One 2009;4:e8013.  Back to cited text no. 59
    
60.
Hung SP, Yang MH, Tseng KF, Lee OK. Hypoxia-induced secretion of TGF-β1 in mesenchymal stem cell promotes breast cancer cell progression. Cell Transplant 2013;22:1869-82.  Back to cited text no. 60
    
61.
Nuschke A. Activity of mesenchymal stem cells in therapies for chronic skin wound healing. Organogenesis 2014;10:29-37.  Back to cited text no. 61
    
62.
Wang Y, Crisostomo PR, Wang M, Markel TA, Novotny NM, Meldrum DR, et al. TGF-alpha increases human mesenchymal stem cell-secreted VEGF by MEK- and PI3-K- but not JNK- or ERK-dependent mechanisms. Am J Physiol Regul Integr Comp Physiol 2008;295:R1115-23.  Back to cited text no. 62
    
63.
Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815-22.  Back to cited text no. 63
    
64.
Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells: A new strategy for immunosuppression? Trends Immunol 2007;28:219-26.  Back to cited text no. 64
    
65.
Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2011;2:34.  Back to cited text no. 65
    
66.
Duffy MM, Pindjakova J, Hanley SA, McCarthy C, Weidhofer GA, Sweeney EM, et al. Mesenchymal stem cell inhibition of T-helper 17 cell- differentiation is triggered by cell-cell contact and mediated by prostaglandin E2 via the EP4 receptor. Eur J Immunol 2011;41:2840-51.  Back to cited text no. 66
    
67.
Sullivan C, Murphy JM, Griffin MD, Porter RM, Evans CH, O'Flatharta C, et al. Genetic mismatch affects the immunosuppressive properties of mesenchymal stem cells in vitro and their ability to influence the course of collagen-induced arthritis. Arthritis Res Ther 2012;14:R167.  Back to cited text no. 67
    
68.
Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007;110:3499-506.  Back to cited text no. 68
    
69.
Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: A potential therapeutic strategy for type 1 diabetes. Diabetes 2008;57:1759-67.  Back to cited text no. 69
    
70.
Volarevic V, Al-Qahtani A, Arsenijevic N, Pajovic S, Lukic ML. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity 2010;43:255-63.  Back to cited text no. 70
    




 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Etiology of Diab...
Introduction
Etiology of Diab...
References

 Article Access Statistics
    Viewed451    
    Printed34    
    Emailed0    
    PDF Downloaded66    
    Comments [Add]    

Recommend this journal