1、Mesenchymal Stem Cells:from Regeneration to CancerPeishan Lia,b,Zheng Gonga,b,Leonard D.Shultzb,and Guangwen Renb,*aThe Key Laboratory of Experimental Teratology,Ministry of Education and Department of Molecular Medicine and Genetics,School of Basic Medical Science,Shandong University,Jinan,Shandong
2、,250012,ChinabThe Jackson Laboratory,Bar Harbor,ME 04609,USAAbstractMesenchymal stem cells(MSCs)are multipotent tissue stem cells that differentiate into a number of mesodermal tissue types,including osteoblasts,adipocytes,chondrocytes and myofibroblasts.MSCs were originally identified in the bone m
3、arrow(BM)of humans and other mammals,but recent studies have shown that they are multilineage progenitors in various adult organs and tissues.MSCs that localize at perivascular sites function to rapidly respond to external stimuli and coordinate with the vascular and immune systems to accomplish the
4、 wound healing process.Cancer,considered as wounds that never heal,is also accompanied by changes in MSCs that parallels the wound healing response.MSCs are now recognized as key players at distinct steps of tumorigenesis.In this review,we provide an overview of the function of MSCs in wound healing
5、 and cancer progression with the goal of providing insight into the development of novel MSC-manipulating strategies for clinical cancer treatment.KeywordsMesenchymal stem cells;Regeneration;Cancer;Wound healing;Tumor microenvironment1.IntroductionMesenchymal stem cells(MSCs)are multipotent progenit
6、or cells with the potential to differentiate into diverse types of tissue cells,including osteoblasts,adipocytes,chondrocytes and myofibroblasts(Keating,2012;Singer&Caplan,2011).This type of tissue stem cell plays an essential role in tissue regeneration and closely interacts with cells of the immun
7、e system in the tissue microenvironment during repair from tissue damage(Le Blanc&Davies,2015;Y.Shi et al.,2012;Uccelli,Moretta,&Pistoia,2008).Recently,MSCs have also emerged as a new player in the tumor microenvironment,contributing to*Corresponding author at:The Jackson Laboratory,Bar Harbor,Maine
8、,USA.Publishers Disclaimer:This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting,typesetting,and review of the resulting proof before it is publis
9、hed in its final citable form.Please note that during the production process errors may be discovered which could affect the content,and all legal disclaimers that apply to the journal pertain.Conflict of Interest StatementThe authors declare that there are no conflicts of interest.HHS Public Access
10、Author manuscriptPharmacol Ther.Author manuscript;available in PMC 2020 August 01.Published in final edited form as:Pharmacol Ther.2019 August;200:4254.doi:10.1016/j.pharmthera.2019.04.005.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscripttumor growth,metastasis and therapeutic res
11、istance(Ridge,Sullivan,&Glynn,2017;Y.Shi,Du,Lin,&Wang,2017).Cancer,regarded as“non-healing wounds”(Dvorak,1986,2015),is believed to take advantage of the regenerative functions of host cells to facilitate local cancer growth,resistance to therapy,and metastases to distant organs(Calvo et al.,2015;Kr
12、all et al.,2018;Sundaram et al.,2017).In this review,we discuss how MSCs participate in distinct stages of wound healing and tumor“wound”progression,and compare the functions and mechanisms of MSCs in these two pathological processes.Understanding how the tumor microenvironmental cues drive MSCs to
13、regenerate tumor“wounds”will facilitate our deeper understanding of MSC biology in distinct steps of cancer progression,thereby supporting development of new cancer treatments that target MSCs.2.Tumors are wounds that do not heal:comparison of wound healing to injury with wound healing in tumorigene
14、sis2.1 Wound healing response to injuryUpon tissue injury,a series of wound healing steps including inflammation,tissue proliferation and remodeling are successively initiated and highly coordinated by the adult tissue cells(Maxson,Lopez,Yoo,Danilkovitch-Miagkova,&Leroux,2012).Blood clotting,or coag
15、ulation,occurs immediately after injury.This is achieved by platelet aggregation and clot formation from fibrinogen-converted fibrin and extracellular matrix(ECM)proteins.Blood clotting serves as the first barrier against blood and water loss as well as invading pathogens.After clot formation,an inf
16、lammation stage is initiated by neutrophil infiltration into the injury sites usually within a few hours but up to one day post injury,and is followed by the arrival of monocytes and mast cells one to two days later.The monocytes differentiate into macrophages,which persist long-term at the tissue s
17、ites until wound healing is complete.Myeloid cell migration is guided by chemotactic substances such as damage-or pathogen-associated molecular patterns(DAMPs or PAMPs),hydrogen peroxide(H2O2)and chemokines,which are released from the damaged tissues and surrounding stroma in response to injury and
18、invading pathogens(de Oliveira,Rosowski,&Huttenlocher,2016).Migration of myeloid cells marks the beginning of the inflammation stage in wound healing from injury.Myeloid cells function to not only phagocytize the dead tissue cells or invading pathogens during the inflammation stage,but also further
19、modulate the next stages of tissue proliferation and remodeling by releasing cytokines,chemokines and other trophic factors(Minutti,Knipper,Allen,&Zaiss,2017).Along with myeloid cell infiltration,adaptive immune cells such as T lymphocytes are also recruited to the injury sites where they specifical
20、ly target pathogens and release cytokines to further regulate inflammation,proliferation and tissue remodeling(Havran&Jameson,2010;Keyes et al.,2016).In the absence of major infection,the inflammatory phase peaks at about two to three days post-injury and gives way to the proliferative phase that la
21、sts about two weeks.Proliferation of three major cell types including epithelial cells(re-epithelialization),mesenchymal cells(fibroplasia)and endothelial cells(revascularization or angiogenesis),occurs concomitantly in the proliferation phase.Through both autocrine and paracrine mechanisms,a pletho
22、ra of Li et al.Page 2Pharmacol Ther.Author manuscript;available in PMC 2020 August 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptcytokines and trophic factors,such as epidermal growth factor(EGF),transforming growth factor beta(TGF),platelet-derived growth factor(PDGF),fibro
23、blast growth factor(FGF)and vascular endothelial growth factor(VEGF),play essential roles in the acceleration of epithelial tissue re-growth,production of collagen and other ECM proteins and formation of new blood vessels(Guo&Dipietro,2010).Following the proliferative phase,tissue remodeling continu
24、es from weeks to years depending on the wound type and size.During tissue remodeling,the disorganized collagen fibers formed during the proliferative phase will rearrange and align along tension lines.Wound contraction occurs in parallel with a reduction in the numbers of macrophages and fibroblasts
25、 and a reduction in blood vessels by apoptosis,which together achieve a successful healing process(Hinz et al.,2012).2.2 Wound healing response to tumorigenesisTumors have long been regarded as wounds that fail to complete the normal three stages of wound healing(Dvorak,1986).During early tumorigene
26、sis,cancer cells are recognized by innate and adaptive immune cell-mediated host surveillance leading to apoptosis and/or necrosis.The dead tumor cells in turn release various DAMPs such as adenosine,high-mobility group box 1 protein(HMGB1),annexins and calreticulin,which serve to initiate the infla
27、mmatory response followed by a cascade of events within the wound healing process(Hernandez,Huebener,&Schwabe,2016).With tumor progression,the surrounding blood vessels become permeable which further triggers platelet and fibrin deposition,and,in turn,starts the program of inflammation,proliferation
28、 and ECM remodeling(Kreuger&Phillipson,2016).As long as tumors are not eradicated by the host immune system or external therapies,the healing steps continue until the tumor burden exceeds the hosts capability to survive.An apparent difference between normal physiological wound healing and tumorigene
29、sis is that the latter possesses one or multiple prolonged,uncompleted phases,and tumors can therefore be considered as an“overhealing wound”(Schafer&Werner,2008).Tumor progression is closely associated with the three phases of wound healing.The first phase,inflammation,a hallmark of cancer,is in fa
30、ct a doubleedged sword in tumor development and therapy responses.The innate and adaptive immune cells are phenotypically and functionally plastic depending on their resident microenvironment.Type 1 immune cells are conventionally activated cells,such as“N1”neutrophils,“M1”macrophages and“Th1”or“Tc1
31、”T cells.These cells are mainly considered to be tumoricidal and exert direct cytotoxic effects against tumor cells.In contrast,the alternatively activated type 2 immune cells function to promote distinct steps in cancer progression through release of multiple cytokines and chemokines(Gabrilovich,Os
32、trand-Rosenberg,&Bronte,2012;Nowarski,Gagliani,Huber,&Flavell,2013).During the second phase,the proliferation phase,angiogenesis(revascularization)and desmoplasia(fibroplasia)coordinately support epithelial tumor growth(re-epithelialization)via a collection of growth factors,which are equally essent
33、ial for wound healing.The third phase,tissue remodeling,completes the wound healing response but fails to be completed in the context of a tumor.However,many of the tissue remodeling activities that occur during wound healing,such as lysyl oxidase(LOX)-induced collagen crosslinking and matrix metall
34、oproteinase(MMP)-mediated collagen rearrangement and alignment,have been Li et al.Page 3Pharmacol Ther.Author manuscript;available in PMC 2020 August 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscriptshown to be pivotal in tumor cell migration,invasion and metastasis,as well as
35、in resistance to therapy(Cox&Erler,2011;P.Lu,Weaver,&Werb,2012).3.In vitro and in vivo identity of mesenchymal stem cellsMSCs are multipotent stem cells that can differentiate into multiple cell lineages including adipocytes,osteoblasts,chondrocytes,tenocytes and myofibroblasts.In the 1960s and 1970
36、s,this type of adult stem cell was initially identified as a population of bone marrow(BM)cells with colony forming capabilities in vitro and osteogenic cell differentiation potential in vivo(Friedenstein,Chailakhjan,&Lalykina,1970;Friedenstein,Petrakova,Kurolesova,&Frolova,1968).In the 1980s and 19
37、90s,these cells were defined as“Mesenchymal Stem Cells”possessing multiple non-hematopoietic mesenchymal lineage cell differentiation capabilities in vitro and in vivo(Caplan,1991;Prockop,1997).Afterwards,MSCs were isolated from almost every tissue in the body(umbilical cord,Whartons jelly,skin,lung
38、,liver,adipose tissue,muscle,dental pulp,etc.)in addition to the BM(da Silva Meirelles,Chagastelles,&Nardi,2006).In recent years,MSCs were also isolated from various tumor tissues as“tumor wounds”could stimulate resident MSC proliferation or recruit circulating MSCs(Karnoub et al.,2007;Ren et al.,20
39、12;Y.Shi et al.,2017).According to criteria by the International Society for Cellular Therapy(ISCT)published in 2006,cultured MSCs should be adherent,fibroblast-like cells with osteogenic,adipogenic and chondrogenic differentiative capacity in vitro.Moreover MSCs must express the surface markers CD1
40、05,CD73 and CD90,but not express CD45,CD34,CD14,CD11b,CD79,CD19 or human leukocyte antigen-DR isotype(HLA-DR)(Dominici et al.,2006).In 2013,ISCT further shared guidelines for the immunological characterization of MSCs,highlighting the functional plasticity of MSCs in the context of different inflamm
41、atory milieus(Krampera et al.,2013).In spite of all these efforts in defining MSCs,the boundaries for delineating MSCs,fibroblasts and pericytes still remain largely illusive due to a lack of specific markers for these cell populations(Caplan,2008;Haniffa,Collin,Buckley,&Dazzi,2009;Keating,2012;Nomb
42、ela-Arrieta,Ritz,&Silberstein,2011).Nevertheless,MSCs were recently described as“Medicinal Signaling Cells”to reflect their multifaceted functions in wound repair rather than considering their stemness properties(Caplan,2017).Based upon their robust capacity in regulating every step of wound healing
43、,cultured MSCs have been applied in over 450 clinical trials to treat degenerative diseases and immune disorders(Maxson et al.,2012;Squillaro,Peluso,&Galderisi,2016).While the clinical application of ex vivo-expanded MSCs in treating diseases has been established,in vivo exploration of endogenous MS
44、Cs has also progressed.Pioneering work by Crisan et al in 2008 demonstrated a perivascular origin of MSCs in multiple human organs.They purified perivascular cells from human skeletal muscle,pancreas,adipose tissue and placenta and showed after long-term culture that these cells maintained the MSC p
45、henotype as well as the trilineage differentiation potential(Crisan et al.,2008).Since then,the endogenous MSCs were believed to reside at perivascular sites in various tissues which may be regarded as a subset of pericytes in vivo(Caplan,2008,2017).Genetic lineage tracing assays were also widely ap
46、plied to identify the differentiation fates of perivascular MSC-like cells in the context of fibrotic diseases and tissue injury models(El Agha et al.,Li et al.Page 4Pharmacol Ther.Author manuscript;available in PMC 2020 August 01.Author ManuscriptAuthor ManuscriptAuthor ManuscriptAuthor Manuscript2
47、017).A series of transgenic mice with Cre/loxP technology have recently been created and applied to explore the cellular hierarchies of the perivascular MSCs,such as Nestin-cre(Mendez-Ferrer et al.,2010;Tronche et al.,1999),myxovirus resistant 1(Mx1)-cre(R.Kuhn,Schwenk,Aguet,&Rajewsky,1995;Park et a
48、l.,2012),Leptin-receptor(Lepr)-cre(Decker et al.,2017;DeFalco et al.,2001;Zhou,Yue,Murphy,Peyer,&Morrison,2014),and glioma-associated oncogene homolog 1(Gli1)-cre(Ahn&Joyner,2004;Kramann et al.,2015;Schneider et al.,2017).Although the differentiation specificity and efficiency of the perivascular MS
49、Cs still remain controversial,most reports support the notion that endogenous MSCs are highly plastic upon tissue injury and give rise to myofibroblasts,osteoblasts or adipocytes in bone,lung,liver,kidney,heart,spinal cord,muscle,and skin depending on the injury types or duration.It is also well acc
50、epted that cells differentiating from endogenous tissue MSCs play a major role in induction of organ or tissue fibrosis(El Agha et al.,2017).In contrast to the extensive studies that recognize the in vivo identity of MSCs in tissue regeneration,far fewer studies have been carried out to determine th
