Mesenchymal stem cells: Properties and clinical potential for cell based therapies in reconstructive surgery with a focus on peripheral nerve surgery
Mesenchymale Stammzellen: Eigenschaften und klinisches Potential für zellbasierte Therapien in der rekonstruktiven Chirurgie mit dem Schwerpunkt der peripheren Nervenchirurgie
Abstract
The isolation and expansion of multipotent mesenchymal stem cells (MSCs) could be demonstrated from bone marrow, peripheral blood,
Jörn W. Kuhbier
1Kerstin Reimers
1skin, umbilical cord blood and adipose issue. They can be differentiated
Bernd Schmitz
1to different mesodermal cell lines like bone, cartilage, muscle or adipose
Peter M. Vogt
1tissue cells in vitro as well as in vivo. Thus MSCs represent an attractive cell population for the substitution of mesenchymal tissues via tissue
Christine Radtke
1engineering due to their potential of differentiation and their favourable expansion properties. In contrast to embryonic stem cells (ESCs) they
have the advantage that they can be autologously harvested in high
1 Department of Plastic, Aesthetic, Hand- andnumbers. Besides, there are fewer ethical issues in the use of MSCs.
Reconstructive Surgery,
Another advantage of MSCs is the highly regenerative secretion profile
Hannover Medical School, Hannover, Germany
of cytokines and growth factors, in particular supporting angiogenesis.
A plethora of studies describe the morphological and phenotypical characterization of this cell type as well as regulatory mechanisms underlying the differentiation into specific tissues aiming to optimize in vitro conditions for differentiation and thus clinical application.
This review describes the definition of a mesenchymal stem cell, methods for isolation and phenotypical characterization, possibilities of differentiation and possible therapeutical applications of MSCs.
Zusammenfassung
Die Isolierung und die Expansion pluripotenter mesenchymaler Stammzellen (MSCs) konnte aus Knochenmark, peripherem Blut, Haut, Nabelschnurblut und Fettgewebe demonstriert werden. Sie können sich zu verschiedenen mesodermalen Zellarten wie Knochen-, Knorpel-, Muskel- oder Fettzellen sowohl in vitro wie auch in vivo differenzieren.
Somit stellen die MSCs aufgrund ihres mesenchymalen Differenzierungs-
potentials und ihrer guten in vitro-Expansionseigenschaften eine attrak-
tive Zellpopulation für den Ersatz mesenchymaler Gewebe für das Tissue
Engineering (TE) dar. Im Gegensatz zu embryonalen Stammzellen (ESCs)
haben sie den Vorteil, dass sie in ausreichend hoher Zellzahl autolog
gewonnen werden können. Darüber hinaus bestehen bei den MSCs
keine ethischen Problemstellungen. Ein weiterer Vorteil von mesenchy-
malen Stammzellen ist ihr hochgradig regeneratives, insbesondere
Angiogenese förderndes Sekretionsprofil von Zytokinen und Wachstums-
faktoren. Eine Vielzahl von Studien beschreibt die morphologische und
phänotypische Charakterisierung dieser Zellart und Regulationsmecha-
nismen bei der Differenzierung in bestimmte Gewebespezifikationen
mit dem Ziel, die in vitro-Konditionen zur Differenzierung zu optimieren
und um somit die klinische Anwendung zu erleichtern.
Dieser Übersichtsartikel beschreibt die Definition der mesenchymalen Stammzellen, die Methoden zur Isolierung und phänotypischen Charak- terisierungen, die Differenzierungsmöglichkeiten und mögliche thera- peutische Anwendungen der MSCs.
Introduction
More than 1.5 million patients in Germany were treated because of degenerative diseases in 2002 [1]. However, many more patients remain untreated aside from the significant demographic change towards an older popu- lation in all western countries. Thus, it is expected that the number of U.S. citizens older than 65 years will double during the next twenty years while the number of citizens older than 85 years will quadruplicate.
Likewise the number of patients in need of treatment because of degenerative diseases will rise. The demand of soft tissue substitute is equally high as a number of 5.6 million patients in the USA alone underwent recon- structive surgery due to trauma or tumor resections in 2012 [2].
In this context, the subcutaneous adipose tissue plays a central role and is the crucial component in reconstructive surgery to restore the superficial surface and shape in an aesthetic fashion [3], [4], [5], [6], [7], [8], [9].
With that being said, there is a need for new therapeutic approaches because autologous transplantations tend to lose up to 40–60% of the original volume [9], [10]. Al- logenic, xenogenic or synthetic materials may cause ad- verse immunological reactions [11], [12]. Considering this, the use of stem cells may be advantageous for autologous tissue engineering as well as cell-based therapies which aim to stimulate endogenous regenera- tive capacities.
The primary purpose of transplanting adult stem cells of different origins is to repair and regenerate the resident tissue after injuries. For this task, the self-renewal prop- erties of stem cells, i.e. division to one daughter cell that will differentiate to a mature, terminally differentiated cell and one new adult stem cell, are a prerequisite. The former, so-called progenitor cell will further divide to build complexes of mature cells while the latter serves as a cell “reserve” for self-renewal.
These stem cells are resident in different tissues, but bone marrow is a renowned source for stem cells.
Derived from the embryonal mesoderm, bone marrow contains two populations of adult stem cells. One popu- lation is the hematopoietic stem cell (HSC) which is re- sponsible for all mature cell lines in peripheral blood.
There is a well-characterized population of cells capable of self-renewal, which produce progenitor cells and are able to differentiate into mature blood cells.
Bone marrow also contains mesenchymal stem or stroma cells (MSCs) which can influence hematopoietic differen- tiation via secretion of cytokines and growth factors.
Likewise, these MSCs are able to differentiate into osteo- genic, chondrogenic, adpiogenic, myogenic and neurogen- ic lineages, i.e. they are capable of transdifferentiation [13].
Despite the recognition of MSCs as stem cells due to their capability of self-renewal and differentiation into different cell lines, it is yet unknown to what extent MSCs are re- sponsible for normal growth and preservation of tissues.
Recent studies raise promising expectations on the po- tential of theses stem cells for future cell-based therapies.
However, in spite of many results it remains challenging to establish a consistent and standardized definition of this type of stem cell. There are different protocols exist- ing for the isolation, identification and differentiation of MSCs.
Definition of stem cells
There are differences between toti- and multipotent stem cells. Zygote embryonic stem cells are totipotent while adult stem cells are multipotent [14], [15]. Totipotency describes the ability to transdifferentiate, i.e. the devel- opment of cells from all three germ layers that is meso- dermal, ectodermal and endodermal differentiation.
Multipotency means the potential to differentiate within one germ layer. Adult multipotent stem cells exist in many tissues, for example in skeletal muscle, in adipose tissue or in bone marrow [16].
The totipotent embryonic stem cells were established in 1998 by Shamblott et al. [17] and Thomson et al. [18].
Despite the particular scientific significance, the applica- tion of this cell population is restricted by ethical and legal reasons. Additionally, histocompatibility or tenden- cies towards degeneracy are not yet clarified.
During isolation of MSCs from different tissues at first a heterogeneous mixture of cells is obtained from which MSCs can be filtered by application of these definitions.
In a position paper from the International Society of Cel- lular Therapy from the year 2006 it is stated that MSCs have the following properties [19]:
1. Adherence on plastic surfaces under standard cell culture conditions
2. Specific phenotype of surface antigens:
Positivity (>95% positive cells) for CD73, CD90 and CD105
Negativity (<2% positive cells) for CD45, CD34, HLA- DR as well as CD14 or CD11b and CD79α or CD19 3. In vitro differentiation in osteogenic, adipogenic or
chondrogenic cell line induced by supplements to cell
culture media (verified by specific histological
stainings)
Figure 1: Light microscopy of undifferentiated ASCs in culture (A) and after differentiation into glia cells with characteristic bipolar- shape morphology. Scale bar in (A) represents 300 µm and pertains to (A) and (B)
Adult mesenchymal stem cells
In 1867 the pathologist Cohnheim suggested for the first time the existence of non-hematopoietic adult stem cells.
In the context of wound healing studies he injected a dye into the blood of testing animals to investigate to what extent dyed cells might be found in the wound. Beside inflammatory cells, which were assigned to the hematopoi- etic system, he found cells with a fibroblast-like morphol- ogy. Accordingly, Cohnheim deducted that the bone marrow has to be a reserve of such cells. In 1976, Friedenstein was successful in isolating the cell type de- scribed by Cohnheim. Friedenstein cultivated bone mar- row cells on untreated culture dishes and waited for 4 hours before he rinsed non-adherent cells. In the culture dishes cells could be observed which were strongly adher- ent and showed a heterogenous morphology. This spindle- shaped cell type formed colonies containing three to four cells. The cell cultures remained inactive for two to four days before an extreme proliferation occurred. In following studies it was shown that this extensive growth is depend- ent on the method of isolation, the density of these stem cells in the bone marrow as well as age and general health condition of the donor [20], [21], [22], [23].
The heterogeneity of the MSC cultures observed by Friedenstein could be confirmed by Conget and Minguell [24]. In that article, it was stated that there is not just one but three different cell types which can be distin- guished:
1. a proliferative-active, big, flat cell,
2. a proliferative-active, spindle-shaped cell and 3. a small, round, self-perpetuating cell.
Colter et al. verified this observation and characterized the different cell types in MSC cultures more precisely [25]. A small amount in the cultures formed the so-called RS-1 cells which display a slender, agranular cellular morphology. Furthermore, those cells have a limited ca- pacity for colony-forming and are negative for Ki-67, a cell-cycle antigen and marker of proliferation. An unprolif- erative cell phenotype is indicated by a slight content of DNA as well as an increased expression of the ornithine-
decarboxylase antizyme [26]. Beside this RS-1 cells, there exists a population of the so-called mMSCs which show a high proliferation rate.
Differentiation potential of adult stem cells
The differentiation potential of adult stem cells was de- scribed at first by the so called predestination theory.
This theory said that tissue- or organ-specific stem cells can just differentiate to terminal cell lines of this potential tissue or organ, respectively. Following this theory, bone marrow stem cells can just differentiate in hematopoetic lines and stem cells derived from the brain into neurogen- ic lines [27], [28]. Regarding BM-MSCs this theory was advanced by Haynesworth et al. [29], Prockop [30] and Pittenger et al. [15]. Those groups could prove that BM- MSCs have the potential to differentiate into mesen- chymal and non-mesenchymal cell lines. BM-MSCs can differentiate into osteogenic [31], [32], [33], chondrogenic [15], [34], [35], adipogenic [15] and myogenic lines [15], [30], [36], [37]. Furthermore, a differentiation to neural tissue [36], [38], [39], [40], [41] and tendon tissue [42], [43] could be induced. The exact mechanism of differen- tiation is as yet unresolved, particularly with regard to neural differentiation [44], [45]. In contrast, for bone marrow-derived MSCs (BM-MSCs) it can be deduced that they can be differentiated into adipogeic, chondrogenic and osteogenic cell lines as e.g. bone itself is steadily remodelling and as necessary in partial recovery e.g. after a fracture [46].
Another, often investigated cell population of MSCs are the so called adipose-derived stem cells (ASCs; Figure 1).
Like BM-MSCs these ASCs have the potential for mesen- chymal and non-mesenchymal differentiation [15]. Hence ASCs could be differentiated into adipocytes, chondro- cytes, osteoblasts, myocytes [47], endothelial cells [48], neuron-like cells [49], [50], [51], hepatocytes [52], [53], pancreatic cells [54] and hematopoietic cells [55].
ASCs offer the advantage to be less traumatic in their
extraction with higher yields.
Moreover adipose tissue accumulates as waste product after liposuctions or dermolipectomies in plastic surgery with the result that here exists a big reservoir for plastic surgical research. Most favourable, stem cells can be isolated in high amounts from adipose tissue – from 1 gram of adipose tissue, 5×10
3ASCs can be isolated, i.e. the 500-fold amount than from 1 gram of bone mar- row [56].
Characterization of MSCs
Beside the multipotent differentiation capability, MSCs from the bone marrow offer other positive properties. In general, they are easy to isolate and cultivate, thereby exhibiting a great potential of proliferation; from a single MSC, up to 7×10
7MSCs can originate until passage 6 and up to 5,5×10
8to 1,2×10
9until passage 10–25 [24], [57]. Moreover, MSCs are not immunocompetent which renders them attractive for allogenic transplantations – no immune response could be seen after MSC transplan- tation between immunocompatible patients in a study by LeBlanc [58].
Collagen type I, type II, fibronectin and laminin could be identified in the extracellular matrix of MSCs [59]. Further- more, interleukins (IL) -6, IL-7, IL-8, IL-11, IL-12, IL-14, IL- 15 and the factors macrophage-colony stimulating factor (M-CSF), leukemia inhibitory factor (LIF) and Skp, Cullin, F-box containing complex (SCF) are secreted. Additionally, MSCs secrete IL-1α, LIF, granulocyte-colony stimulating factor (G-SCF) and granulocyte macrophage-colony stimulating factor [60], [61], [62].
MSCs are not only influenced by the prevailing microen- vironment, but do influence the microenvironment as well [63]. It was shown that MSCs influence hematopoiesis [64], [65]. A significant issue is the so-called stem cell niche, i.e. a specific microenvironment with corresponding contacts between cells and extracellular matrix which is considered in recent publications as a determinant con- cerning the question whether a cell with unlimited cap- acity of self renewal is a stem cell or a cancer cell [66], [67].
BM-MSC as well as ASCs express the marker STRO-1 which is a marker of multilineage progenitor cells from the bone marrow [68], [69]. Zuk et al. could find two markers by which a distinction between the two ASCs and BM-MSCs is possible: CD 49d (α4 integrin) and CD 106 (vascular cell adhesion molecule; VCAM). ASCs are posi- tive for CD 49d and BM-MSCs are not, and vice versa for the marker CD106 [70].
Future therapy alternatives
From a therapeutical point of view, MSCs allow attractive approaches. Kopen et al. injected MSCs in the lateral ventricle of mice [41]. It could be observed that those cells were integrated into brain tissue, adopted the mor- phology of astrocytes and expressed glial fibrillary acidic
protein (GFAP). In some cells, there was even expression of the protein neuronal nuclei (NeuN), indicating a neur- onal differentiation [41]. Beside this systemic or local transplantation, the use of MSCs in genetic therapy was suggested. Keating et al. showed that MSCs, which were transfected with the gene for factor IX and implanted in vivo, secreted this factor for certain time periods – which outlines an interesting therapeutical approach for hemo- philia B [59]. Based on the therapy models presented herein, approaches for several diseases could be de- veloped, for example for facial nerve repair [71], [72], osteogenesis imperfecta [73], [74], degenerative arthritis [75] or multiple sclerosis [76].
Tissue engineering
Tissue engineering (TE) displays an alternative therapy in this context. If a patient needs repair of a long nerve defect (>3 cm), there are different methods possible:
1. Autologous nerve transplantation, for example the sural nerve
2. Allogenic nerve transplantation
3. Implantation of an artificial biocompatible nerve con- duit
However, there are certain limitations to these strategies.
Autologous nerve transplants show pathological changes in many cases and are available only in limited amounts.
Allogenic nerve transplants can lead to immune re- sponses in terms of host-versus-graft reaction. Artificial biocompatible nerve conduits in contrast are prone to loosen, to rupture, to dislocate or to interact with the surrounding tissue in terms of regeneration-inhibiting scar tissue [9]. TE aims to preserve functionally active cells that support development of new tissue inside a biological scaffold by secretion of growth factors [57], [76], [77], [78], [79], [80], [81], [82].
The basic principles of TE can be described as follows:
1. Healthy cells are required that a.) are not immunogenic, b.) can be isolated easily,
c.) show a high proliferative capacity, i.e. are respon- sible to external stimuli (for example growth factors).
2. There have to be carriers existing that can support cell differentiation in vitro and can be transplanted afterwards.
3. Bioactive molecules are required that are able to in- duce and control cell differentiation and maturation [83], [84], [85].
Regarding this, stem cells as such are of particular in-
terest for TE purposes as these cells own the capability
for unlimited self-renewal and may undergo differentiation
processes [86], [87]. It can be stated that within the
scope of TE the ideal cell should be immunocompatible,
self-perpetuating and capable of differenitiation or
transdifferentiation, respectively. Moreover, the ideal
source or resort should be easy to access, be available
Table 1: Secretion of growth factors by MSCs (for VEGF additional measurement in normal (basal) and hypoxic conditions) [88]
to a great extent and be dispensable without limitation of function of the donor organism. Regarding these re- quirements for cell and tissue for TE, the advantages of ASC in contrast to BM-MSC become apparent.
Regenerative potential of mesenchymal stem cells
Beside the direct advantages of stem cells as cell popu- lations used for TE, MSCs display a highly regenerative secretion profile. The growth factors released by MSCs are highly angiogenic, the values for some of the most significant are depicted in Table 1 [88]. Considerably, the secretion of angiogenic growth factors increases substan- tially if ASCs are cultured under hypoxic conditions. For example, the value for vascular endothelial growth factor (VEGF) raises under hypoxic conditions up to the 5-fold of the value under normal conditions [88].
Stem cells for nerve regeneration
Experimental cell transplantations were utilized success- fully to support axonal regeneration of spinal cords axons that usually have minimal regenerative properties [89], [90].
In these studies satisfying functional results could be obtained, for that reason such therapies seem promising for clinical approaches [91], [92].
Thereby, MSC-based transplantations as supplement for nerve reconstruction were considered for several reasons:
These cells support the guidance of the outgrowing axons and deliver trophic support for the spinal cord which en- ables spinal cord axons to regenerate. To combine nerve repair with the additive application of myelin-forming cells is a relatively simple, fast and efficient method to support peripheral nerve regeneration as well [93], [94], [95], [96], [97].
Substantial issues are released neurotrophic growth factors like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF) as well as Neurotropin-3 and -4 (NT-3 and -4) [98], [99].
For functional nerve regeneration, not only axonal sprouting and elongation of neurites are necessary but also a remyelination with adequate expression of ion channels in the region of Ranvier’s nodes to restore ap-
propriate nerve conduction velocity. Consequently, remyelination is a prerequisite for recovery of normal nerve conduction velocity on the one hand and protection of axons against degenerative processes on the other hand.
If in an acute nerve lesion myelin-forming cells are transplanted, they are already activated for myelin forming at the point of transplantation while resident Schwann cells have to be activated in a signal cascade. Moreover, damaged spinal dorsal root nerve cells are protected by MSCs from apoptosis [100].
In different studies, glial as well as neuronal differenti- ation of ASCs could be shown in vitro ([101], [102], [103], [104], [105], [106], [107], Figure 1A.
By induction with FGF and EGF, ASCs developed typical morphological and phenotypical characteristics of neurospheres while subsequent deprivation of both resulted in glial differentiation [108], [109]. However, when administered at the site of nerve injury in vivo, they remain undifferentiated and do not differentiate into neuronal cells [110], [111], [112]. They enhance peripher- al nerve regeneration by secretion of BDNF, NGF and FGF and also prevent dorsal root ganglia neurons from under- going apoptosis [113], [100]. In multiple studies, their regenerative effect on peripheral nerve injuries could be shown either by administration of ASCs either locally by injection or on a tubular or scaffold or systemic [93], [95], [96], [97], [99], [107], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133]. For more detailed information, see Table 2.
These results implicate innovative therapy strategies for the treatment of demyelinating diseases as well as trau- matic nerve lesions. The advantage of neuronal and glial differentiation of ASCs regarding clinical application is the relatively simple and less invasive isolation of ASCs compared to the more invasive isolation of bone marrow.
Preliminary works depict that direct as well as intravenous
transplantation of MSCs in lesions of the spinal cord
result in a “homing” of these cells into the lesion and lead
to a considerable reparation in terms of axonal regenera-
tion and remyelination in the central nervous system
[115], [134]. The combination of surgical nerve suture
and transplantation of myelin-forming cells that support
axonal regeneration and remyelinate demyelinated axons
displayed a significant advantage compared to the control
groups without cell transplantation [135].
Table 2: Summary of in vivo-studies on the applications of adipose derived stem cells in the therapy of peripheral nervous system disorders
(Continued)
Table 2: Summary of in vivo-studies on the applications of adipose derived stem cells in the therapy of peripheral nervous system disorders
Conclusions
Adult stem cells from adipose tissue not only have the capability of mesodermal differentiation but also the po- tential of transdifferentiation.
These ASCs meet all criteria that are of essential import- ance for TE and thus have a great potential for regenera- tive medicine. They are easy to harvest in plastic surgical standard procedures, which makes adipose tissue an attractive source for these multipotent cells.
Furthermore, other possible applications with promising
results exist via cell-based therapies in terms of trans-
plantation of MSCs due to their most favourable secretion
profile of cytokines and trophic factors. Positive results
could be achieved by injecting ASCs to the local site of
injury, however, intravenous injection seems also to be
promising. Considering this, ASCs might play a substantial
role in future regenerative medicine, in particular concern-
ing nerve regeneration approaches.
List of abbreviations
ASCs – adipose-derived stem cells BDNF – brain-derived neurotrophic factor bFGF – basic fibroblast growth factor
BM-MSCs – bone marrow-derived mesenchymal stem cells
CD – cluster of differentiation dASC – differentiated ASC EGF – epithelial growth factor FGF – fibroblast growth factor
GDNF – glial-derived neurotrophic factor GFAP – glial fibrillary acidic protein
GGT – genipin-gelatin-tricalcium phosphate
GM-CSF – granulocyte/macrophage-colony stimulating factor
G-CSF – granulocyte-colony stimulating factor HA hydrogel – hydroxyapatite hydrogel hASC – human ASC
HGF – hepatocyte growth factor HSCs – hematopoietic stem cells IL – interleukin
LIF – leukemia inhibitory factor
MCAO – middle cerebral artery occlusion M-CSF – macrophage-colony stimulating factor MSCs – mesenchymal stem cells
NGF – nerve growth factor NeuN – neuronal nuclei
nNOS – neuronal nitric oxide synthase NT – neurotropin
PCL – nolycaprolacton
PLGA – poly(lactic-co-glycolic acid) SC – Schwann cells
SCF – Skp, Cullin, F-box containing complex TE – tissue engineering
TGF-β – transforming growth factor β VEGF – vascular endothelial growth factor
Notes
Acknowledgement
This work has been supported by the Boehringer Ingel- heim Foundation. We thank Sankaranarayanan Sivakmar for support in literature review.
Competing interests
The authors declare that they have no competing in- terests.
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Corresponding author:
Professor Christine Radtke, MD
Department of Plastic, Aesthetic, Hand- and Reconstructive Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany, Phone:
+49 (511) 532 - 8864, Fax: +49 (511) 532 - 8890 Radtke.christine@mh-hannover.de
Please cite as
Kuhbier JW, Reimers K, Schmitz B, Vogt PM, Radtke C. Mesenchymal stem cells: Properties and clinical potential for cell based therapies in reconstructive surgery with a focus on peripheral nerve surgery. GMS Ger Plast Reconstr Aesthet Surg. 2015;5:Doc04.
DOI: 10.3205/gpras000032, URN: urn:nbn:de:0183-gpras0000326
This article is freely available from
http://www.egms.de/en/journals/gpras/2015-5/gpras000032.shtml Published:2015-08-04
Copyright
©2015 Kuhbier et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.
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