J Ayub Med Coll Abbottabad 2002; 14(1) pp 30-33

REVIEW ARTICLE

SCHWANN CELLS: LEADER OF NERVENKITT

Muhammad Mirajullah and Shen Xinya*

Department of Anatomy, Ayub Medical College, Abbottabad, Pakistan & *Shanghai Medical University, P.R. China

INTRODUCTION

Schwann cells (SC) are the major & only glial cell element of peripheral nervous system (PNS) which by virtue of their unique biological activities give the distinction of regeneration not only to the peripheral nervous system (PNS) but also induce regeneration in the central nervous system (CNS) by changing the hostile & inhospitable environments around its neurons to neurite promoting favourable conditions. These multifunctional cells synthesize, secrete & express many neurotrophic, neurotropic, neurite promoting & growth factors, major myelin glycoproteins, cell adhesive molecules (CAMs), basement membrane components as well as a cornucopia of receptors at various stages of life. Their important role in neural tissue development, organization & maintenance cannot overshadow their emerging vital contributions to the ongoing studies on demyelinating diseases (e.g. multiple sclerosis) & other debilitating and disfiguring neurological defects  (e.g. neurofibromatosis). Underlying SC defects may be responsible for abnormalities in peripheral neuropathies. SC are the primary cells in the disfiguring disease of neurofibromatosis as well as shoulder the responsibility for Schwannoma & Neurilemoma tumours. Their versatility is evidenced by their phagocytic nature during Wallerian & traumatic degeneration. They are indispensable to the normal functioning of axons. Inhibiting their proliferation at the stage of regeneration not only retards axonal growth but profoundly impairs myelination. Their proliferation & physical presence is a prerequisite for the reparative process providing a proper terrain or scaffolding essential for the regeneration & survival of neurons.

HISTORICAL PERSPECTIVE

In the last more than one and a half century, since the recognition of SC in 1839 through the monumental work of the great German anatomist Theodor Schwann1, tremendous work has been done to reveal the potential biological functions of the SC, but perhaps much more is left for the bicentennial celebrations of the cell. The story dates back to Theodor Schwann's attempts to study the cellular nature of living organisms & his claim that the fatty sheath of the peripheral nerve had a cellular nature & was not an amorphous entity. Although invention of the Electron Microscope settled the controversy in favour of SC but it opened a new era of conflicting findings, which will continue to keep the 21st century investigators sweating well into the near future.

Since the pioneering work of in vitro nervous tissue culture by Harrison (1906) and others, many investigators cultured a variety of tissues & cells2. It was in the middle of this century, among attempts by various laboratories to study the morphological & intracellular aspects, based on the ingenious work of Murray & Stout3 who cultured the non-neuronal cells of adult & embryonic human peripheral nerves, that the miraculous nature of the Schwann cells came into the limelight.

Owing to the development of these cell culture techniques, SC have been isolated from many sources: human, rodent, reptile and avian; adult, young, neonate, fetus and embryo; fresh, cryopreserved and autopsy material. Despite distinct morphological features, SC have a long list of immunocytochemical markers to their credit as well.

REGENERATIVE ROLE

The great versatility of SC reaction to nerve injuries4 is suggestive of the fact that these cells make significant, vital, decisive & multifaceted contributions to the recovery & restoration of functions of injured axons. Although the question whether the SC are the leaders or the followers during nerve regeneration is still un-resolved5-7 but looking at the evidences provided by many excellent studies, the balance seems to be tilting in favour of the former role 8. Viable SC are now proved to be a prerequisite for successful regeneration to occur in the nervous system by providing the trophic support for regrowing axons & establishing a regenerative milieu9-11. It has been reported that freeze dried acellular nerve grafts do not engender axon growth10,12 & inhibiting SC co-migration with regenerating peripheral nerve axons into an acellular graft significantly impedes neurite out-growth12. Peripheral nerves & Retinal Ganglion Cells do extend neurites for some distance into peripheral nerve grafts devoid of SC but far less than in the presence of SC10,12. It has also been reported that preventing SC proliferation during regeneration retards the nerve regenerative capacity. The large number of SC (transplanted or proliferated by trauma) & their advantageous position, as well as their ability to present their own surfaces, basal lamina & multiple secretory activity count for their extraordinary ability to foster axonal resurgence in an effective manner9.

In addition to its regenerative potential for PNS, SC when transplanted into CNS in the form of isolated cultured cells or as  peripheral nerve grafts, induce the potentially capable CNS axons to regenerate by converting the unfriendly & iniquitous cellular milieu13,14 of CNS (presence of oilgodendrocytes, astrocytes, CNS myelin, TN, lack of basal lamina components & other neurotrophic & neurotropic factors)  into a regenerative favouring microenvironment4, 15-17.

MECHANISM OF REGENERATION

SC have the remarkable capacity to induce regeneration in the PNS as well as in the CNS when they are transplanted as isolated purified cells suspension, as a spreadsheet on collagen rolls, as a heterogenous cell population, in the form of a nerve segment, or even SC conditioned medium. SC influence the regenerating neurites in more than one way.  They have been reported to function as the presidential motorcade for the resurging neurites to make the pathway by their proteolytic & susbstratum carpeting actions. Many of the neurotrophic substances have been reported to direct the axonal regrowth by targetting receptor sites on neurite growth cones18,19.

Irrespective of the close relationship between functional status or type & their regenerative activities20, the SC in whatever form they are presented, induce pronounced neurite outgrowth. The Wallerian degeneration within hours reprograms the traumatic site for axonal regeneration by stimulation of rapid proliferation of SC21 (probably macrophage mediated); migration of SC from both stumps (predominantly proximal); preferential axonal growth along interfaces of basal lamina (BL) & SC surfaces; and reexpression of CAMs8,22,23 (L1, N-CAM) & Extracellular Matrix Molecules [Laminin  (LMN) & Tennacin (TN) accumulated at axon SC contact surfaces] by upregulating their mRNA. Antibodies against L1significantly inhibits this growth. Re-expression of CAMs  has been indicated as the primary factor behind the significant post-transection regeneration. These events are further added to by increases in production of NGF & other NTFs24. BL tubes, in absence of SC, can support nerve regeneration25 but not as effectively as in the presence of SC. SC also respond to trauma by changing their phenotype26 thereby aiding to turn the degenerating nerve segment into an environment that would support regeneration of neurons; nonetheless the phagocytic role for SC has been reported long before in many animals.

SYNTHETIC FUNCTIONS

SC synthesize some of the most important Neurotrophic Factors (NTFs) & Growth Factors (GFs) like Nerve Growth Factor, Brain Derived Neurotrophic Factor, Ciliary Neurotrophic Factor, Fibroblast Growth Factor,

Interstitial Growth Factor, and Platelet Derived Growth Factor27-30, reexpress a galaxy of receptors for many NTFs, Neurite Promoting Factors (NPFs) & GFs30-32; elaborate Cell Adhesive Molecules (CAMs)4; and synthesize, secrete & assemble basal membrane (BM) components9,18 & apolipoproteins33. The neurotrophic requirements for cells (motor, sensory & sympathetic) contributing to the formation of peripheral nerves differ among them but SC & only the SC produce all these factors to effectively help regenerate the peripheral nerve axons34. The SC conditioned extracellular fluid has been reported to stimulate SC proliferation, adhesion & migration5,35. Recently a novel NPA has been reported34, not particular for any class of neuron, in the SC from adult rat Sciatic Nerve & immortal SC clone which is not related to all of the previously known NTFs/NPFs, indicating a new cytokine or a novel NTF or combinatorial effect of the known NTFs. Leaving aside the NTFs, GFs, NPFs, CAMs, & BL components, they present perhaps the most abundant receptor sites on their surfaces. They synthesize Growth Associated Protein (GAP)36, express c-met mRNA37, Glia Fibrillary Associated Protein (GFAP) & myelin proteins38, POU/SCIP39, c-jun40,41, enzymes42 & SCF43.

OTHER FUNCTIONS

In fact, SC neurite regenerating potentials have unjustifiably overshadowed their other so many unique & singular contributions to the development of the nervous system, its regeneration, reorganization & proper coordinated functioning. They have automitogenic activity44,45 in long term cultures, while autoinhibitory action in short term cultures46,47. They are extensively involved in neurite directionality. The range of their fostering neurotrophic activities involves a wide range of cells including dopaminergic neurons, sensory, motor (both PNS & CNS) & sympathetic cells34,48. They  are indispensable for the proper functions of rapid axonal conduction, axonal protection, maintenance & formation of myelin, remyelination of injured PNS as well as CNS axons49, regulation of axoplasmic flow & metabolic activities. The myelin sheath, in addition to its insulating & conduction facilitating actions, is closely related to the molecular exchanges between axon & extracellular compartment.

CONCLUDING REMARKS

When one looks at the unbelievable synthesizing & expressing potentials of the SC, it leaves little doubt about their versatile functions. Also worth mentioning is their changing scenario of functional activities under different conditions. They promptly change their expressing activities & phenotypic characteristics at different stages of life as & when required.

Some other glial (astrocytes) & non-glial (macrophages) cells, reportedly play roles in the regenerative process but neither of them as well as none of the other glial cells can snatch the credit which for almost a century belongs to SC & would remain to give the distinction to them in the future50. None of the other glial cells have ever attempted to interfere in the domain of SC. These are the daring efforts of the SC which have effectively & successfully encroached upon the CNS boundaries by challenging the hostile resident cues. SC deserve to be crowned as the true candidate for leading the team of glia.

Looking at the efforts on SC transplantation & their evaluation to determine the extent of SC as a therapeutic tool, for alleviating the impoverishing miseries caused by the nervous system injuries or certain incurable diseases with unknown aetiology, it does not seem too distant that the SC would one day assume the role of an established therapeutic agent for incapacitating & paralyzing disabilities. We should join our hands to bring that day "tomorrow".

REFERENCES

1.        Schwann T.  Mikroskopische untersuchungen uber die uebereinstimmung in der struktur und dem wachstum der tiere und pflanzen. Sander. Berlin, 1839.

2.        Lim R and Bosch P. Isolation of astrocytes and Schwann cells for culture. In: Cell Culture (Coon PM Ed.), Academic Press CA.;1990:47-55.

3.        Murray MR & Stout AP. Characteristics of human Schwann cells in vitro. Anat Rec,1940;84:293-95.

4.        Martini R. Expression and functional roles of N-CAMs and Extracellular Matrix  components during development and regeneration of peripheral nerves. J Neurocyt, 1994;23:1-28.

5.        LeBeau JM, Ellisman MH, & Powell HC. Ultrastructural and morphometric analysis of long-term peripheral nerve regeneration through silicone tubes. J Neurocyt, 1988;17:161-72.

6.        Anderson PN, Nadim W, & Turmaine M. Schwann Cells migration through freeze killed peripheral nerve grafts without accompanying axons. Acta Neuropathol, 1991;82:193-9.

7.        Keynes RJ. Schwann Cells during neural development and regeneration: Leaders or followers? TINS, 1987;10:137-9.

8.        Bailey SB, Eichler ME, Villadiego A, & Rich KM. The influence of Fibronectin & Laminin during Schwann Cells migration and peripheral nerve regeneration through silicon chambers. J Neurocyt, 1993;22:176-84.

9.        Bunge MB, Bunge RP, Kleitman N, & Dean AC. Role of peripheral nerve extracellular matrix in Schwann Cell function and in neurite regeneration. Dev Neurosci, 1989;11:348-60.

10.      Berry M, Rees L, Hall S, Yiu P, & Sievers J. Optic axons regeneration into Sciatic Nerve isografts only in the presence of Schwann Cells. Brain Res Bull, 1988;20(2):223-31.

11.      Smith GV, & Stevenson JA. Peripheral nerve grafts lacking viable Schwann Cells fail to support CNS axonal regeneration. Exp Brain Res, 1986;69:299-306.

12.      Gulati AK. Evaluation of acellular and cellular nerve grafts in repair of rat peripheral nerve. J Neurosurg, 1988;68:117-23.

13.      Carpenter MK et al. CNS white matter can be altered to support neuronal outgrowth. J Neurosci Res, 1994;37:1-14.

14.      Gue'nard V, Aebischer P, & Bunge RP. The astrocytes inhibition of peripheral nerve regeneration is reversed by Schwann Cells. Exp Neurol, 1994;126:44-60.

15.      Maffei L et al. Schwann Cells promote the survival of rat ganglion cells after Optic Nerve section. PNAS, USA, 1990;87:1855-9.

16.      Schwab ME, & Caroni P. Oligodendrocytes & CNS myelin are non-permissive substrates for neurite growth & Fibroblast spreading in vitro. J Neurocyt,1988;8:2381-93.

17.      Paino CL, & Bunge MB. Induction of axon growth into Schwann Cell implants grafted in to lesioned adult rat spinal cord. Exp Neurol, 1991;114:254-7.

18.      Tohyama K, & Ide C. The localization of Laminins and Fibronectin on the Schwann Cell Basal Lamina. Archs Histol Jpn, 1986;49:519-32.

19.      Thoenen H. The changing scene of Neurotrophic Factors. TINS, 1991;14:165-70.

20.      Bähr M, Eschweiler GW, & Wolburg H. Precrushed Sciatic Nerve grafts enhance the survival and axonal regrowth of Retinal Ganglion Cells in adult rats. Exp Neurol, 1992;116:13-22.

21.      Fawcett JW, & Keynes RJ. Peripheral nerve regeneration. Annu Rev Neurosci, 1990;13:43-60.

22.      Kuecherer-Ehret A, et al. Immunoelectron microscopic localization of Laminin in normal and regenerating mouse Sciatic Nerve. J Neurocyt, 1990;19:101-9.

23.      Wang G-Y. Behavior of axons, SC, & perineurial cells in nerve regeneration with in transplanted nerve grafts: Effects of anti-Laminin & anti-Fibronectin antisera. Brain Res, 1992;583:216-26.

24.      Tedeschi B, & Liuzzi FJ. Axotomized frog Sciatic Nerve releases diffusible Neurite Promoting Factors. Dev Brain Res, 1992;97:107-23.

25.      Ide C. Nerve regeneration and Schwann Cell Basal Lamina: Observations of the long term regeneration. Arch Histol Jpn, 1983;46:243-51.

26.      Reichert F, Saada A, & Rotshenker S. Peripheral nerve injury induces Schwann Cells to express two macrophage phenotypes: Phagocytosis and the galactose-specific lectin MAC-2. J Neurosci, 1994;14(5):3231-45.

27.      Notter MFD et al. Primate Schwann Cells express multiple growth factors in vitro. Soc Neurosci Abstr, 1991;17:1502.

28.      Neuberger TJ & DeVries GH. Distribution of Fibroblast Growth Factor in cultured Dorsal Root Ganglia neurons and Schwann Cells. I. Localization during maturation in vitro. J Neurocyt, 1993;22:436-48.

29.      Neuberger TJ, & DeVries GH. Distribution of Fibroblast Growth Factor in cultured Dorsal Root Ganglia neurons & Schwann Cells. II. Redistribution after neural injury. J Neurocyt, 1993;22(6):449-60.

30.      Hardy M, Reddy UR, & Pleasure D. PDGF and regulation of Schwann Cell proliferation in vivo. J Neurosci Res, 1992;31:254-62.

31.      Taniuchi M, Clark HB, & Johnson(Jr) EM. Induction of Nerve Growth Factor in Schwann Cells after axotomy. PNAS, USA, 1986;83:4094-8.

32.      Jung-Testas I, Schumacher M, Bugnard H, & Baulieu EF. Stimulation of rat Schwann Cell proliferation by estradiol: Synergism between the estrogen and cAMP. Dev Brain Res, 1993;72:282-90.

33.      Ignatius MJ et al. Expression of apolipoprotein E during nerve degeneration and regeneration. PNAS USA, 1986;83:1125-9.

34.      Bolin LM, & Shooter EM. Characterization of a Schwann Cell neurite promoting activity that directs motoneuron axon outgrowth. J Neurosci Res, 1994;37(1):23-35.

35.      LeBeau JM et al. Extracellular fluid conditioned during peripheral nerve regeneration stimulates Schwann Cell adhesion, migration, & proliferation. Brain Res, 1988;459:93-104.

36.      Plantinga LC et al. The expression of B-50 / GAP-43 in Schwann Cells is upregulated in  degenerating distal nerve. Soc Neurosci Abstr, 1992;18:432.

37.      Krasnoselsky A et al. H Growth Factor is a mitogen for Schwann Cells and is present in NF. J Neurosci, 1994;14(12):7284-91.

38.      Pareek S et al. Detection and regulation of PMP-22mRNA and protein in cultured Schwann Cells. Soc Neurosci Abstr, 1992;18:1490

39.      Scherer SS et al. Axons regulate Schwann Cells expression of the POU transcription factor SCIP. J Neurosci, 1994;14(4):1930-42.

40.      Shy ME et al. Axonal regulation of C-jun expression in Schwann Cells in vivo. Soc Neurosci Abstr, 1992;18:1089.

41.      Vaudano E et al. Expression of C-jun protein in Schwann Cells depends on their environment. Soc Neurosci Abstr, 1992;18:765.

42.      Constable AL et al. Production of prostanoids by Lewis rat Schwann Cells in vitro. Brain Res, 1994;635:75-80.

43.      Ryan JJ et al.  Role for the SCF/KIT complex in Schwann Cells neoplasia and mast cell proliferation associated with neurofibromatosis. J Neurosci Res, 1994;37:415-32.

44.      Porter S, Glaser L, and Bunge RP. Release of autocrine growth factor by primary and immortalized Schwann Cells. PNAS, USA, 1987;84:7768-72.

45.      Eldridge CF, & Bunge RP. Normal Schwann Cells release a factor which stimulates normal Schwann Cell proliferation. Anat Rec, 1987;218:40a.

46.      Muir D, and Varon S. Activation of stromyelsin is required for autocrine inhibition of Schwann Cell proliferation. Soc Neurosci Abstr, 1991;17:932.     

47.      Eccleston PA, Jessen KR, &  Mirsky R. Spontaneous immortalization of Schwann Cells in culture: short-term cultured Schwann Cells secrete growth inhibitory activity. Development, 1991;112:33-42.

48.      Gu Li Qiang, and Zhu Jia Kai. Experimental study of the Schwann Cell derived Neurotrophic Factors. Chinese J Microsurg, 1993;16(2):125-8.

49.      Fine A. Transplantation in the CNS. In " The Biology of Brain: From Neuron to Network  (Llna's RR ed.), WH Freeman & Company, NY, 1988;149-160.

50.      Mirajullah M. Studies on Schwann Cells cultures: the potential role in peripheral nerve regeneration along with Laminin in SD albino rats. Ph.D (Neuroanatomy) thesis. Shanghai Medical University, 1995