285:
Potential targets for tumor-associated stromal cell recruitment have been identified in the following host tissue: bone marrow, connective tissue, adipose tissue, and blood vessels. Moreover, evidence suggests that tumor-associated stroma are a prerequisite for metastasis and tumor cell invasion. These are known to arise from at least six different origins: immune cells, macrophages, adipocytes, fibroblasts, pericytes, and bone marrow mesenchymal stromal cells. Furthermore, the tumor stroma is primarily composed of the basement membrane, fibroblasts, extracellular matrix, immune cells, and blood vessels. Typically, most host cells in the stroma are characterized by tumor-suppressive abilities. However, during malignancy, the stroma will undergo alterations to consequently incite growth, invasion, and metastasis. These changes include the formation of carcinoma-associated fibroblasts (CAFs) which comprises a major portion of the reactive tissue stroma and plays a critical role in regulating tumor progression.
281:
non-reactive stromal cells, TASCs secrete increased levels of proteins and matrix metalloproteinases (MMPs). These proteins include fibroblast activating protein and alpha-smooth muscle actin. Furthermore, TASCs secrete many pro-tumorigenic factors such as vascular endothelial growth factor (VEGF), stromal-derived factor-1 alpha, IL-6, IL-8, tenascin-C, and others. These factors are known to recruit additional tumor and pro-tumorigenic cells. The cross-talk between the host stroma and tumor cells is essential for tumor growth and progression. Tumor stromal production exhibits similar qualities as normal wound repair such as new blood vessel formation, immune cell and fibroblast infiltration, and considerable remodeling of the extracellular matrix.
340:
MSCs can affect cells of the adaptive immune system as well as cells of the innate immune system. For example, they can inhibit the proliferation and activity of T-cells When there is a high level of MSCs during an immune response the generation of more B-cells is stunted. The B-cells that can still
280:
During normal wound healing processes, the local stromal cells change into reactive stroma after altering their phenotype. However, under certain conditions, tumor cells can convert these reactive stromal cells further and transition them into tumor-associated stromal cells (TASCs). In comparison to
284:
Additionally, the recruitment of local normal host stromal cells, such as bone marrow mesenchymal stromal cells, endothelial cells, and adipocytes, help create a conspicuously heterogeneous composition. Furthermore, these cells secrete an abundance of factors that help regulate tumor development.
361:
in order to regulate the growth and activity of other immune system cells as well as blood cells. Furthermore, MSCs can polarize macrophages towards a more immunosuppressive M2 phenotype. The mechanisms through which MSCs affect cells of the immune system can be contact-dependent or mediated by
158:. This keeps the epidermis regenerating from the bottom while the top layer of cells on the epidermis are constantly being "sloughed" off the body. Additionally, stromal cells play a role in inflammation responses, and controlling the amount of cells accumulating at an inflamed region of tissue.
478:
which are an inhibitor of the immune response. They also do not carry receptors that relate to the immune system or are not in high enough concentrations to admit a response. This is helpful for the future of MSC cell therapies because there will be little to no negative effects from a possible
423:
instead of cytotoxic T-cells. However, if the levels of IFN-gamma and TNF-alpha are low the MSCs produce low levels of IDO and therefore can activate T-cells normally and the inflammation process takes place. MSCs with +IL-6 in the presence of monocytes induce M2-macrophages and CCL-18 which
166:
Defining a stromal cell is of importance because it was a source of difficulty in the past. Without a strong definition studies could not cross over or gain knowledge from each other because a stromal cell was not well defined and went by a plethora of names. A stromal cell is currently more
362:
secreted substances. An example for a contact-dependent mechanism is the expression of programmed death-ligand 1 (PD-L1), through which MSCs can suppress T cells. The secreted substances MSCs release an inflammatory response is stimulated include for example nitric oxide (NO),
424:
inhibits T-cells from being activated. However, MSCs with -IL-6 in the presence of monocytes induce M1-macrophages and can activate T-cells and produce high levels of IFN-gamma and TNF-alpha which regulates the inflammation through the previously mentioned mechanism.
436:
and other blood elements are formed. Stromal cells play a large role in the distinction of hematopoietic cells (cells that can differentiate into other blood cells). MSCs act as a physical support for differentiating hematopoietic cells in conjunction with the
507:. Most research of these cells have been done in controlled laboratory environments which can sometimes alter the effects seen. The potentials, however, for cell therapy in tissue repair, immune modulation, and anti-tumor agent distribution are promising.
390:
Stromal cells are most often looked at for their hypoimmunogenic response but they are actually non specific immunomodulating. MSCs can flip the switch between anti-inflammatory and pro-inflammatory based on their levels of IFN-gamma,
336:
can be overstimulated during an ongoing immune response, but stromal cells help to keep the balance and make sure the body can properly heal without an excessive amount of inflammation. Thereby, they also help prevent autoimmunity.
1160:
Davies, L. C., Heldring, N., Kadri, N. & Le Blanc, K. Mesenchymal
Stromal Cell Secretion of Programmed Death-1 Ligands Regulates T Cell Mediated Immunosuppression. Stem cells (Dayton, Ohio) 35, 766-776, doi:10.1002/stem.2509
407:(TLR's). This triggers inflammatory mediators and activates either pro- or anti-inflammatory MSCs. If IFN-gamma and TNF-alpha are present in high levels the MSCs will stimulate an anti-inflammatory response by activating
503:). Stromal cells have the unique ability to create an immune modulated environment in order to best respond to foreign and known particles. The reason for halted use of MSCs is the lack of knowledge of the cells
739:
Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The
International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317, doi:10.1080/14653240600855905
195:
but not all therefore it can not be broadly termed a stem cell. All MSCs have the ability adhere to plastic and replicate by themselves. The minimal criteria to define MSCs further include a specific set of
602:
Fixe P, Rougier F, Ostyn E, Gachard N, Faucher JL, Praloran V, Denizot Y (March 1997). "Spontaneous and inducible production of macrophage colony-stimulating factor by human bone marrow stromal cells".
1170:
Strauch, V. et al. N-glycosylation controls inflammatory licensing-triggered PD-L1 upregulation in human mesenchymal stromal cells. Stem cells (Dayton, Ohio) 38, 986-993, doi:10.1002/stem.3190 (2020)
252:
in forming the elements of the blood. While a majority is found in the bone marrow scientists now know that stromal cells can be found in a variety of different tissues as well. These can include
474:
MSCs have the potential to be used in multiple disease interventions. One important feature of MSCs is that they can go virtually undetected by the immune system. The stromal cells possess
449:
that influence the hematopoietic cells differentiation. The body tells the MSCs what blood elements are needed and it conveys those adhesion molecules to the differentiating cell.
630:
Lorgeot V, Rougier F, Fixe P, Cornu E, Praloran V, Denizot Y (October 1997). "Spontaneous and inducible production of leukaemia inhibitory factor by human bone marrow stromal cells".
349:
behavior. Dendritic cells in the presence of MSC's are immature and undifferentiated which causes impaired function to call upon T-cells and bridge the gap between the
292:) cannot spread throughout the body because the cancer cells require nearby stromal cells to continue their division. The loss of these stromal growth factors when the
119:
through multiple pathways. They also aid in differentiation of hematopoietic cells and forming necessary blood elements. The interaction between stromal cells and
492:
272:. High quality stromal cells are located in the placenta, due to their young age. MSCs lose function with age, and aged MSCs are less efficacious in therapy.
516:
536:
200:. The cells must express CD73, CD90 and CD105 and they must be negative for CD14 or CD11b, CD34, CD45, CD79 alpha or CD19 and HLA-DR. Low levels of
299:
Stroma is made up of the non-malignant cells, but can provide an extracellular matrix on which tumor cells can grow. Stromal cells may also limit
754:
1479:
Dazzi, Francesco MD, PhD. Mesenchymal stromal cells: a mechanistic overview. Video
Journal of Hematological Oncology. King's College London.
920:"The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer"
1148:
Le Blanc, K., Mougiakakos, D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev
Immunol 12, 383–396 (2012).
1401:
969:"Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes"
1092:
Park, Chae Woon; Kim, Keun-Soo; Bae, Sohyun; Son, Hye Kyeong; Myung, Pyung-Keun; Hong, Hyo Jeong; Kim, Hoeon (May 2009).
496:
102:
204:(HLA-DR) make MSCs hypoimmunogenic. MSCs have trilineage differentiation capacity where they are able to adapt into
1558:
382:
inhibiting T cell proliferation and activity by tryptophan depletion and by kynurenine-mediated suppression.
179:. Being a mesenchymal cell indicates an ability to develop into various other cell types and tissues such as
17:
1235:
374:
can stimulate the expression of these immunoregulatory mediators like IDO. IDO catalyzes the conversion of
715:
585:
363:
37:
found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become
1389:
1342:
1016:
Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002).
967:
Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, et al. (September 2011).
197:
136:
245:
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500:
453:
249:
201:
918:
Bremnes RM, Dønnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, et al. (January 2011).
432:
Before differentiation a majority of MSCs are housed within the bone marrow which is also where
175:, and self-replicating. These factors make it an effective tool in potential cell therapies and
354:
1453:
1388:
Luzzani, C.; Miriuka, S. G. (2017-01-01), Bolontrade, Marcela F.; García, Mariana G. (eds.),
1251:
463:
392:
229:
168:
1563:
1037:"The development and function of dendritic cell populations and their regulation by miRNAs"
551:
488:
480:
438:
350:
289:
683:
666:
8:
333:
316:
An important property of MSCs is their ability to suppress an excessive immune response.
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555:
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370:(PGE2), programmed death-ligand 1 (PD-L1) and many more. Inflammatory cytokines like
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38:
953:
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371:
367:
188:
147:
869:"Tumor-associated stromal cells as key contributors to the tumor microenvironment"
1423:
936:
919:
771:
475:
458:
225:
221:
42:
1431:
1094:"Cytokine Secretion Profiling of Human Mesenchymal Stem Cells by Antibody Array"
1203:
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151:
140:
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Stromal cells are an important part of the body's immune response and modulate
34:
1480:
1109:
1052:
885:
1552:
1521:
1424:"Mesenchymal stromal cells for COVID-19: A living systematic review protocol"
1366:
1309:
1259:
1212:
1117:
1060:
830:
780:
667:"Stromal cells in chronic inflammation and tertiary lymphoid organ formation"
442:
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1002:
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184:
172:
116:
1496:
Horwitz, Edwin M.; Andreef, Michael; Frassoni, Francesco (November 2006).
1374:
867:
Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC (August 2016).
805:
Ullah, Imran; Subbarao, Raghavendra
Baregundi; Rho, Gyu Jin (2015-04-28).
651:
616:
296:
moves throughout the body prevents the cancer from invading other organs.
257:
241:
209:
139:), bone marrow stromal cells have been described to be involved in human
120:
77:
61:
53:
1390:"4 - Mesenchymal Stem/Stromal Cells Derived From Pluripotent Stem Cells"
1341:
Morrison, Sean J.; Uchida, Nobuko; Weissman, Irving L. (November 1995).
822:
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for the hematopoietic cell to continue to develop. Lastly, MSCs express
303:
proliferation via nitric oxide production, hindering immune capability.
433:
379:
375:
346:
329:
205:
73:
65:
807:"Human mesenchymal stem cells - current trends and future prospective"
1301:
420:
213:
192:
107:
81:
984:
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342:
269:
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responses allowing for the potential to help with a broad range of
128:
57:
1187:"Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation"
1149:
966:
504:
1422:
Rada, Gabriel; Corbalán, Javiera; Rojas, Patricio (2020-04-18).
1234:
Takeda, Kiyoshi; Kaisho, Tsuneyasu; Akira, Shizuo (April 2003).
866:
537:"Stromal effects on mammary gland development and breast cancer"
240:
It is well known that stromal cells arise and are stored in the
321:
317:
300:
293:
124:
49:
46:
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immune response. There is promising research in the fields of
917:
665:
Buckley CD, Barone F, Nayar S, Bénézech C, Caamaño J (2015).
416:
132:
89:
69:
412:
76:
cells of that organ. The most common stromal cells include
755:"Immunomodulatory properties of mesenchymal stromal cells"
664:
408:
127:
growth and progression. In addition, by regulating local
357:
immune responses. These dendritic cells instead release
1015:
629:
601:
1495:
1340:
1185:
Bernardo, Maria Ester; Fibbe, Willem E. (2013-10-03).
1394:
Mesenchymal
Stromal Cells as Tumor Stromal Modulators
517:
List of human cell types derived from the germ layers
146:
Stromal cells (in the dermis layer) adjacent to the
33:, or mesenchymal stromal cells, are differentiating
1284:Bianco, Paolo; Robey, Pamela Gehron (2000-06-15).
716:"What are Stromal Cells (Mesenchymal Stem Cells)?"
72:. They are cells that support the function of the
1421:
1233:
1550:
804:
1347:Annual Review of Cell and Developmental Biology
753:Nauta, Alma J.; Fibbe, Willem E. (2007-11-15).
1387:
1184:
1091:
1396:, Boston: Academic Press, pp. 103–119,
1481:https://www.youtube.com/watch?v=5xXy7gQjDfg
1283:
534:
441:. Stromal cells also provide nutrients and
306:
235:
92:
1022:Molecular Biology of the Cell. 4th Edition
752:
469:
161:
1529:
1343:"The Biology of Hematopoietic Stem Cells"
1317:
1202:
1125:
1068:
992:
935:
894:
884:
838:
770:
682:
571:
248:. They are located in the stroma and aid
1252:10.1146/annurev.immunol.21.120601.141126
427:
403:. Pathogens are initially recognized by
341:be produced are impacted by diminished
191:. Some stromal cells can be considered
14:
1551:
1034:
1491:
1489:
1290:The Journal of Clinical Investigation
1279:
1277:
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1176:
684:10.1146/annurev-immunol-032713-120252
862:
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710:
708:
706:
704:
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311:
150:(the top layer of the skin) release
1359:10.1146/annurev.cb.11.110195.000343
1098:International Journal of Stem Cells
497:acute respiratory distress syndrome
385:
27:Connective tissue cell of any organ
24:
1514:10.1097/01.moh.0000245697.54887.6f
1486:
1274:
1173:
25:
1575:
1035:Zhou, Haibo; Wu, Li (July 2017).
855:
795:
743:
699:
275:
123:is known to play a major role in
171:(MSC). It is non-hematopoietic,
1473:
1415:
1381:
1334:
1227:
1164:
1154:
1150:https://doi.org/10.1038/nri3209
1142:
1085:
1028:
1009:
960:
911:
535:Wiseman BS, Werb Z (May 2002).
288:Certain types of skin cancers (
733:
658:
623:
595:
528:
167:specifically referred to as a
13:
1:
1502:Current Opinion in Hematology
522:
937:10.1097/JTO.0b013e3181f8a1bd
924:Journal of Thoracic Oncology
772:10.1182/blood-2007-02-069716
143:and inflammatory processes.
108:
7:
1498:"Mesenchymal Stromal Cells"
1432:10.1101/2020.04.13.20064162
1286:"Marrow stromal stem cells"
1240:Annual Review of Immunology
671:Annual Review of Immunology
510:
364:indoleamine 2,3-dioxygenase
10:
1580:
1204:10.1016/j.stem.2013.09.006
1018:"T Cells and MHC Proteins"
491:as well as wound healing,
268:and fluid, as well as the
101:
1110:10.15283/ijsc.2009.2.1.59
1053:10.1007/s13238-017-0398-2
886:10.1186/s13058-016-0740-2
605:European Cytokine Network
464:Multipotent stromal cells
307:Immunomodulatory effects
236:Sources of stromal cells
216:. They can also display
169:mesenchymal stromal cell
1559:Connective tissue cells
564:10.1126/science.1067431
470:Use in future therapies
454:Stroma (disambiguation)
202:human leukocyte antigen
162:Defining a stromal cell
1461:Cite journal requires
873:Breast Cancer Research
644:10.1006/cyto.1997.0225
97:, "bed covering", and
93:
428:Role in hematopoiesis
345:count production and
290:basal cell carcinomas
244:until maturation and
230:inflammatory diseases
45:, for example in the
1236:"Toll-Likereceptors"
489:rheumatoid arthritis
481:autoimmune disorders
439:extracellular matrix
334:natural killer cells
198:cell surface markers
823:10.1042/BSR20150025
556:2002Sci...296.1046W
405:toll-like receptors
250:hematopoietic cells
1041:Protein & Cell
811:Bioscience Reports
485:multiple sclerosis
447:adhesion molecules
1403:978-0-12-803102-5
1296:(12): 1663–1668.
973:Nature Immunology
765:(10): 3499–3506.
312:Anti-inflammatory
266:amniotic membrane
264:, dental tissue,
218:anti-inflammatory
181:connective tissue
39:connective tissue
16:(Redirected from
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386:Pro-inflammatory
368:prostaglandin E2
226:immune disorders
189:lymphatic tissue
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459:Stroma of ovary
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131:networks (e.g.
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1191:Cell Stem Cell
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276:Role in cancer
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262:synovial fluid
254:adipose tissue
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