Skip to main content

Advertisement

Log in

The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Although the primary cause of Duchenne muscular dystrophy (DMD) is a genetic mutation, the inflammatory response contributes directly to severity and exacerbation of the diaphragm muscle pathology. The omentum is a lymphoid organ with unique structural and immune functions serving as a sanctuary of hematopoietic and mesenchymal progenitors that coordinate immune responses in the peritoneal cavity. Upon activation, these progenitors expand and the organ produces large amounts of growth factors orchestrating tissue regeneration. The omentum of mdx mouse, a DMD murine model, is rich in milky spots and produces growth factors that promote diaphragm muscle regeneration. The present review summarizes the current knowledge of the omentum as an important immunologic structure and highlights its contribution to resolution of dystrophic muscle injury by providing an adequate environment for muscle regeneration, thus being a potential site for therapeutic interventions in DMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

Ang-1:

Angiopoietin 1

CALT:

Coelomic-associated lymphoid tissue

DMD:

Duchenne muscular dystrophy

HEV:

High endothelial venules

ICAM-1:

Intercellular adhesion molecule 1

IRF4:

Interferon regulatory factor 4

LTIC:

Lymphoid tissue inducer cells

LT-α:

Lymphotoxin alpha

MadCAM-1:

Mucosal vascular addressing cell adhesion molecule-1

M-CSF:

Macrophage colony-stimulating factor

MDSC:

Myeloid-derived suppressor cells

MIP-1α:

Macrophage inflammatory protein 1 alpha

omFALCs:

Omentum fat-associated lymphocyte clusters

PPARγ:

Peroxisome proliferator-activated receptor gamma

RAG-1:

Recombination activating gene 1

RALDH:

Retinaldehyde dehydrogenase

RANTES:

Regulated on activated, normal T cell expressed and secreted

SDF-1α:

Stromal cell-derived factor 1 alpha

STAT:

Signal transducers and activators of transcription

α4β7:

Alpha-4-beta-7 integrin

αLβ2/LFA-1:

Alpha-L-beta-2/Leucocyte function-associated antigen-1

Tyr:

Tyrosine kinase

VCAM:

Vascular cell adhesion molecule

VEGF:

Vascular endothelial growth factor

References

  • Abu-Hijleh MF, Habbal OA, Moqattash ST (1995) The role of the diaphragm in lymphatic absorption from the peritoneal cavity. J Anat 186(Pt 3):453–467

    PubMed  PubMed Central  Google Scholar 

  • Agabiti-Rosei C, Trapletti V, Piantoni S, Airo P, Tincani A, De Ciuceis C, Rossini C, Mittempergher F, Titi A, Portolani N, Caletti S, Coschignano MA, Porteri E, Tiberio GAM, Pileri P, Solaini L, Kumar R, Ministrini S, Agabiti Rosei E, Rizzoni D (2018) Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery. PLoS One 13(5):e0197178

    PubMed  PubMed Central  Google Scholar 

  • Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10(3):165–177

    CAS  PubMed  Google Scholar 

  • Bani C, Lagrota-Candido J, Pinheiro DF, Leite PE, Salimena MC, Henriques-Pons A, Quirico-Santos T (2008) Pattern of metalloprotease activity and myofiber regeneration in skeletal muscles of mdx mice. Muscle Nerve 37(5):583–592

    CAS  PubMed  Google Scholar 

  • Benezech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, Zhang Y, Nayar S, Jones LH, Flores-Langarica A, McIntosh A, Marshall J, Barone F, Besra G, Miles K, Allen JE, Gray M, Kollias G, Cunningham AF, Withers DR, Toellner KM, Jones ND, Veldhoen M, Nedospasov SA, McKenzie ANJ, Caamano JH (2015) Inflammation-induced formation of fat-associated lymphoid clusters. Nat Immunol 16(8):819–828

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berberich S, Dahne S, Schippers A, Peters T, Muller W, Kremmer E, Forster R, Pabst O (2008) Differential molecular and anatomical basis for B cell migration into the peritoneal cavity and omental milky spots. J Immunol 180(4):2196–2203

    CAS  PubMed  Google Scholar 

  • Birukova AA, Alekseeva E, Mikaelyan A, Birukov KG (2007) HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway. FASEB J 21(11):2776–2786

    CAS  PubMed  Google Scholar 

  • Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C, Mathis D (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155(6):1282–1295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buscher K, Wang H, Zhang X, Striewski P, Wirth B, Saggu G, Lütke-Enking S, Mayadas TN, Ley K, Sorokin L, Song J (2016) Protection from septic peritonitis by rapid neutrophil recruitment through omental high endothelial venules. Nat Commun 7(1):1–7

    Google Scholar 

  • Carlow DA, Gold MR, Ziltener HJ (2009) Lymphocytes in the peritoneum home to the omentum and are activated by resident dendritic cells. J Immunol 183(2):1155–1165

    CAS  PubMed  Google Scholar 

  • Chen X, Wu Y, Wang L (2013) Fat-resident Tregs: an emerging guard protecting from obesity-associated metabolic disorders. Obes Rev 14(7):568–578

    CAS  PubMed  Google Scholar 

  • Cipolletta D (2014) Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 142(4):517–525

    CAS  PubMed  PubMed Central  Google Scholar 

  • Conroy MJ, Maher SG, Melo AM, Doyle SL, Foley E, Reynolds JV, Long A, Lysaght J (2018) Identifying a novel role for fractalkine (CX3CL1) in memory CD8(+) T cell accumulation in the omentum of obesity-associated cancer patients. Front Immunol 9:1867

    PubMed  PubMed Central  Google Scholar 

  • Cruz-Migoni S, Caamaño J (2016) Fat-associated lymphoid clusters in inflammation and immunity. Front Immunol 7:612 https://doi.org/10.3389/fimmu.2016.00612

  • Cui L, Johkura K, Liang Y, Teng R, Ogiwara N, Okouchi Y, Asanuma K, Sasaki K (2002) Biodefense function of omental milky spots through cell adhesion molecules and leukocyte proliferation. Cell Tissue Res 310(3):321–330

    CAS  PubMed  Google Scholar 

  • De Paepe B, De Bleecker JL (2013) Cytokines and chemokines as regulators of skeletal muscle inflammation: presenting the case of Duchenne muscular dystrophy. Mediat Inflamm 2013:540370 https://doi.org/10.1155/2013/540370

  • de Senzi Moraes Pinto R, Ferretti R, Moraes LH, Neto HS, Marques MJ, Minatel E (2013) N-Acetylcysteine treatment reduces TNF-alpha levels and myonecrosis in diaphragm muscle of mdx mice. Clin Nutr 32(3):472–475

    PubMed  Google Scholar 

  • De Siena R, Balducci L, Blasi A, Montanaro MG, Saldarelli M, Saponaro V, Martino C, Logrieco G, Soleti A, Fiobellot S, Madeddu P, Rossi G, Ribatti D, Crovace A, Cristini S, Invernici G, Parati EA, Alessandri G (2010) Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism. Exp Cell Res 316(11):1804–1815

    PubMed  Google Scholar 

  • Demoule A, Divangahi M, Danialou G, Gvozdic D, Larkin G, Bao W, Petrof BJ (2005) Expression and regulation of CC class chemokines in the dystrophic (mdx) diaphragm. Am J Respir Cell Mol Biol 33(2):178–185

    CAS  PubMed  Google Scholar 

  • Di Nicola V (2019) Omentum a powerful biological source in regenerative surgery. Regen Ther 182–191 https://doi.org/10.1016/j.reth.2019.07.008

  • Dinulovic I, Furrer R, Handschin C (2017) Plasticity of the muscle stem cell microenvironment. Adv Exp Med Biol 1041:141–169

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dux K (1986) Proliferative activity of macrophages in the greater omentum of the mouse in relation to the early postnatal development of the vascular structures. J Leukoc Biol 40(4):445–458

    CAS  PubMed  Google Scholar 

  • Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9(3):162–174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goldsmith HS (2004) The evolution of omentum transposition: from lymphedema to spinal cord, stroke and Alzheimer's disease. Neurol Res 26(5):586–593

    PubMed  Google Scholar 

  • Grounds MD, Radley HG, Lynch GS, Nagaraju K, De Luca A (2008) Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 31(1):1–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gutpell KM, Hrinivich WT, Hoffman LM (2015) Skeletal muscle fibrosis in the mdx/utrn+/− mouse validates its suitability as a murine model of Duchenne muscular dystrophy. PLoS One 10(1):e0117306

    PubMed  PubMed Central  Google Scholar 

  • Ha SA, Tsuji M, Suzuki K, Meek B, Yasuda N, Kaisho T, Fagarasan S (2006) Regulation of B1 cell migration by signals through Toll-like receptors. J Exp Med 203(11):2541–2550

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kawamura M, Miyagawa S, Fukushima S, Saito A, Miki K, Ito E, Sougawa N, Kawamura T, Daimon T, Shimizu T, Okano T, Toda K, Sawa Y (2013) Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart. Circulation 128(11 Suppl 1):S87–S94

    PubMed  Google Scholar 

  • Li H, Li J (2003) Development of the peritoneal lymphatic stomata and lymphatic vessels of the diaphragm in mice. Ann Anat 185(5):411–418

    PubMed  Google Scholar 

  • Litbarg NO, Gudehithlu KP, Sethupathi P, Arruda JA, Dunea G, Singh AK (2007) Activated omentum becomes rich in factors that promote healing and tissue regeneration. Cell Tissue Res 328(3):487–497

    CAS  PubMed  Google Scholar 

  • Macedo FI, Eid JJ, Decker M, Herschman B, Negussie E, Mittal VK (2018) Autogenous hepatic tissue transplantation into the omentum in a novel ectopic liver regeneration murine model. J Surg Res 223:215–223

    PubMed  Google Scholar 

  • Manay P, Khajanchi M, Prajapati R, Satoskar R (2014) Pedicled omental and split skin graft in the reconstruction of the anterior abdominal wall☆. Int J Surg Case Rep 3:161–163

    Google Scholar 

  • Mebius RE (2009) Lymphoid organs for peritoneal cavity immune response: milky spots. Immunity 30(5):670–672

    CAS  PubMed  Google Scholar 

  • Meza-Perez S, Randall TD (2017) Immunological functions of the omentum. Trends Immunol 38(7):526–536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Michailova KN (2001) Postinflammatory changes of the diaphragmatic stomata. Ann Anat 183(4):309–317

    CAS  PubMed  Google Scholar 

  • Moat SJ, Bradley DM, Salmon R, Clarke A, Hartley L (2013) Newborn bloodspot screening for Duchenne muscular dystrophy: 21 years experience in Wales (UK). Eur J Hum Genet 21(10):1049–1053

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1999) Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33(6):1379–1384

    CAS  PubMed  Google Scholar 

  • Nakamura T, Mizuno S (2010) The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci 86(6):588–610

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nilsson I, Rolny C, Wu Y, Pytowski B, Hicklin D, Alitalo K, Claesson-Welsh L, Wennstrom S (2004) Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development. FASEB J 18(13):1507–1515

    CAS  PubMed  Google Scholar 

  • Okabe Y, Medzhitov R (2014) Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157(4):832–844

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7(5):359–371

    CAS  PubMed  Google Scholar 

  • Paiva-Oliveira EL, da Silva RF, Bellio M, Quirico-Santos T, Lagrota-Candido J (2017) Pattern of cardiotoxin-induced muscle remodeling in distinct TLR-4 deficient mouse strains. Histochem Cell Biol 148(1):49–60

    CAS  PubMed  Google Scholar 

  • Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ (2004) Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103(5):1662–1668

    CAS  PubMed  Google Scholar 

  • Pinheiro DF, da Silva RF, Carvalho LP, Paiva-Oliveira EL, Pereira RS, Leite PE, de Fatima Pinho M, Quirico-Santos T, Lagrota-Candido J (2012) Persistent activation of omentum influences the pattern of muscular lesion in the mdx diaphragm. Cell Tissue Res 350(1):77–88

    CAS  PubMed  Google Scholar 

  • Pinheiro DF, da Silva RF, Barbosa TM, Gama JFG, Gomes AC, Quirico-Santos T, Lagrota-Candido J (2019) Omentum acts as a regulatory organ controlling skeletal muscle repair of mdx mice diaphragm. Cell Tissue Res 377(2):1–11 https://doi.org/10.1007/s00441-019-03012-y

  • Pinho Mde, Hurtado SP, El-Cheikh MC, Borojevic R (2005) Haemopoietic progenitors in the adult mouse omentum: permanent production of B lymphocytes and monocytes. Cell Tissue Res 319(1):91–102

  • Platell C, Cooper D, Papadimitriou JM, Hall JC (2000) The omentum. World J Gastroenterol 6(2):169–176

    PubMed  PubMed Central  Google Scholar 

  • Rangel-Moreno J, Moyron-Quiroz JE, Carragher DM, Kusser K, Hartson L, Moquin A, Randall TD (2009) Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30(5):731–743

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rizvanov AA, Persson J, Sahin F, Bellusci S, Oliveira PJ (2016) Hematopoietic and mesenchymal stem cells in biomedical and clinical applications. Stem Cells Int 2016:3157365

    PubMed  PubMed Central  Google Scholar 

  • Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM (2017) Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med 6(12):2173–2185

    PubMed  PubMed Central  Google Scholar 

  • Saqib NU, McGuire PG, Howdieshell TR (2010) The omentum is a site of stromal cell-derived factor 1alpha production and reservoir for CXC chemokine receptor 4-positive cell recruitment. Am J Surg 200(2):276–282

    CAS  PubMed  Google Scholar 

  • Shadmani A, Kazemi K, Khalili MR, Eghtedari M (2014) Omental transposition in treatment of severe ocular surface alkaline burn: an experimental study. Med Hypothesis Discov Innov Ophthalmol 2:57–61

    Google Scholar 

  • Shah S, Lowery E, Braun RK, Martin A, Huang N, Medina M, Sethupathi P, Seki Y, Takami M, Byrne K, Wigfield C, Love RB, Iwashima M (2012) Cellular basis of tissue regeneration by omentum. PLoS One 7(6):e38368

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shudo Y, Miyagawa S, Fukushima S, Saito A, Shimizu T, Okano T, Sawa Y (2011) Novel regenerative therapy using cell-sheet covered with omentum flap delivers a huge number of cells in a porcine myocardial infarction model. J Thorac Cardiovasc Surg 142(5):1188–1196

    PubMed  Google Scholar 

  • Singh AK, Patel J, Litbarg NO, Gudehithlu KP, Sethupathi P, Arruda JA, Dunea G (2008) Stromal cells cultured from omentum express pluripotent markers, produce high amounts of VEGF, and engraft to injured sites. Cell Tissue Res 332(1):81–88

    CAS  PubMed  Google Scholar 

  • Singh AK, Pancholi N, Patel J, Litbarg NO, Gudehithlu KP, Sethupathi P, Kraus M, Dunea G, Arruda JA (2009) Omentum facilitates liver regeneration. World J Gastroenterol 15(9):1057–1064

    PubMed  PubMed Central  Google Scholar 

  • Solvason N, Kearney JF (1992) The human fetal omentum: a site of B cell generation. J Exp Med 175(2):397–404

    CAS  PubMed  Google Scholar 

  • Tidball JG, Villalta SA (2010) Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298(5):R1173–R1187

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ugel S, Delpozzo F, Desantis G, Papalini F, Simonato F, Sonda N, Zilio S, Bronte V (2009) Therapeutic targeting of myeloid-derived suppressor cells. Curr Opin Pharmacol 9(4):470–481

    CAS  PubMed  Google Scholar 

  • Vatansev C, Ustun ME, Ogun CO, Tastekin G, Karabacakoglu A, Yilmaz H (2003) Omental transposition decreases ischemic brain damage examined in a new ischemia model. Eur Surg Res 35(4):388–394

    CAS  PubMed  Google Scholar 

  • Vernik J, Singh AK (2007) Omentum: power to heal and regenerate. Int J Artif Organs 30(2):95–99

    CAS  PubMed  Google Scholar 

  • Villalta SA, Nguyen HX, Deng B, Gotoh T, Tidball JG (2009) Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet 18(3):482–496

    CAS  PubMed  Google Scholar 

  • Villalta SA, Rinaldi C, Deng B, Liu G, Fedor B, Tidball JG (2011) Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum Mol Genet 20(4):790–805

    CAS  PubMed  Google Scholar 

  • Villalta SA, Rosenthal W, Martinez L, Kaur A, Sparwasser T, Tidball JG, Margeta M, Spencer MJ, Bluestone JA (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6(258):258ra142

    PubMed  PubMed Central  Google Scholar 

  • Westenfelder C (2014) Does the greater omentum (“policeman of the abdomen”) possess therapeutic utility in CKD? J Am Soc Nephrol 6:1133–1135

    Google Scholar 

  • Wijffels JF, Hendrickx RJ, Steenbergen JJ, Eestermans IL, Beelen RH (1992) Milky spots in the mouse omentum may play an important role in the origin of peritoneal macrophages. Res Immunol 143(4):401–409

    CAS  PubMed  Google Scholar 

  • Wilkosz S, Ireland G, Khwaja N, Walker M, Butt R, de Giorgio-Miller A, Herrick SE (2005) A comparative study of the structure of human and murine greater omentum. Anat Embryol (Berl) 209(3):251–261

    Google Scholar 

  • Wu D, Han JM, Yu X, Lam AJ, Hoeppli RE, Pesenacker AM, Huang Q, Chen V, Speake C, Yorke E, Nguyen N, Sampath S, Harris D, Levings MK (2019) Characterization of regulatory T cells in obese omental adipose tissue in humans. Eur J Immunol 49(2):336–347

    CAS  PubMed  Google Scholar 

  • Yildirim A, Aktas A, Nergiz Y, Akkus M (2010) Analysis of human omentum-associated lymphoid tissue components with S-100: an immunohistochemical study. Romanian J Morphol Embryol 51(4):759–764

    CAS  Google Scholar 

  • Yiu EM, Kornberg AJ (2015) Duchenne muscular dystrophy. J Paediatr Child Health 51(8):759–764

    PubMed  Google Scholar 

Download references

Funding

This study was supported by grants from FAPERJ (Fundação de Amparo à Pesquisa do Rio de Janeiro), PROPPI (UFF), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jussara Lagrota-Candido.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care Committee CEUA UFF (protocol numbers 171, 717, and 1054) and conducted according to the Conselho Nacional de Controle de Experimentação Animal, CONCEA.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gama, J.F.G., Pinheiro, D.F., Da Silva, R.F. et al. The omentum harbors unique conditions in the peritoneal cavity to promote healing and regeneration for diaphragm muscle repair in mdx mice. Cell Tissue Res 382, 447–455 (2020). https://doi.org/10.1007/s00441-020-03238-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-020-03238-1

Keywords

Navigation