274:
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.
270:
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.
329:
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
269:
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
273:
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.
350:
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
147:. 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.
467:
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
412:
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
155:
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
351:
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),
413:
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.
425:
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
496:. 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.
379:
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,
325:
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.
1149:
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
396:(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
492:). 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
728:
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
184:
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
591:
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".
1159:
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)
241:
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
463:
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
438:
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.
619:
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".
338:
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
281:) 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
108:
through multiple pathways. They also aid in differentiation of hematopoietic cells and forming necessary blood elements. The interaction between stromal cells and
481:
261:. 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.
505:
525:
189:. 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
288:
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
743:
1468:
Dazzi, Francesco MD, PhD. Mesenchymal stromal cells: a mechanistic overview. Video
Journal of Hematological Oncology. King's College London.
909:"The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer"
1137:
Le Blanc, K., Mougiakakos, D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev
Immunol 12, 383–396 (2012).
1390:
958:"Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes"
1081:
Park, Chae Woon; Kim, Keun-Soo; Bae, Sohyun; Son, Hye Kyeong; Myung, Pyung-Keun; Hong, Hyo Jeong; Kim, Hoeon (May 2009).
485:
91:
193:(HLA-DR) make MSCs hypoimmunogenic. MSCs have trilineage differentiation capacity where they are able to adapt into
1547:
371:
inhibiting T cell proliferation and activity by tryptophan depletion and by kynurenine-mediated suppression.
168:. Being a mesenchymal cell indicates an ability to develop into various other cell types and tissues such as
1224:
363:
can stimulate the expression of these immunoregulatory mediators like IDO. IDO catalyzes the conversion of
704:
574:
352:
26:
found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become
1378:
1331:
1005:
Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002).
956:
Lukacs-Kornek V, Malhotra D, Fletcher AL, Acton SE, Elpek KG, Tayalia P, et al. (September 2011).
186:
125:
234:
1455:
489:
442:
238:
190:
907:
Bremnes RM, Dønnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, et al. (January 2011).
421:
Before differentiation a majority of MSCs are housed within the bone marrow which is also where
164:, and self-replicating. These factors make it an effective tool in potential cell therapies and
343:
1442:
1377:
Luzzani, C.; Miriuka, S. G. (2017-01-01), Bolontrade, Marcela F.; García, Mariana G. (eds.),
1240:
452:
381:
218:
157:
1552:
1026:"The development and function of dendritic cell populations and their regulation by miRNAs"
540:
477:
469:
427:
339:
278:
672:
655:
8:
322:
305:
An important property of MSCs is their ability to suppress an excessive immune response.
1347:
544:
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359:(PGE2), programmed death-ligand 1 (PD-L1) and many more. Inflammatory cytokines like
206:
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27:
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1302:
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628:
556:
548:
360:
356:
177:
136:
858:"Tumor-associated stromal cells as key contributors to the tumor microenvironment"
1412:
925:
908:
760:
464:
447:
214:
210:
31:
1420:
1083:"Cytokine Secretion Profiling of Human Mesenchymal Stem Cells by Antibody Array"
1192:
1175:
1006:
314:
254:
250:
242:
140:
129:
104:
Stromal cells are an important part of the body's immune response and modulate
23:
1469:
1098:
1041:
874:
1541:
1510:
1413:"Mesenchymal stromal cells for COVID-19: A living systematic review protocol"
1355:
1298:
1248:
1201:
1106:
1049:
819:
769:
656:"Stromal cells in chronic inflammation and tertiary lymphoid organ formation"
431:
389:
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144:
87:
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681:
632:
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173:
161:
105:
1485:
Horwitz, Edwin M.; Andreef, Michael; Frassoni, Francesco (November 2006).
1363:
856:
Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC (August 2016).
794:
Ullah, Imran; Subbarao, Raghavendra
Baregundi; Rho, Gyu Jin (2015-04-28).
640:
605:
285:
moves throughout the body prevents the cancer from invading other organs.
246:
230:
198:
128:), bone marrow stromal cells have been described to be involved in human
109:
66:
50:
42:
1379:"4 - Mesenchymal Stem/Stromal Cells Derived From Pluripotent Stem Cells"
1330:
Morrison, Sean J.; Uchida, Nobuko; Weissman, Irving L. (November 1995).
811:
434:
for the hematopoietic cell to continue to develop. Lastly, MSCs express
292:
proliferation via nitric oxide production, hindering immune capability.
422:
368:
364:
335:
318:
194:
62:
54:
796:"Human mesenchymal stem cells - current trends and future prospective"
1290:
409:
202:
181:
96:
70:
973:
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331:
258:
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responses allowing for the potential to help with a broad range of
117:
46:
1176:"Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation"
1138:
955:
493:
1411:
Rada, Gabriel; Corbalán, Javiera; Rojas, Patricio (2020-04-18).
1223:
Takeda, Kiyoshi; Kaisho, Tsuneyasu; Akira, Shizuo (April 2003).
855:
526:"Stromal effects on mammary gland development and breast cancer"
229:
It is well known that stromal cells arise and are stored in the
310:
306:
289:
282:
113:
38:
35:
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immune response. There is promising research in the fields of
906:
654:
Buckley CD, Barone F, Nayar S, Bénézech C, Caamaño J (2015).
405:
121:
78:
58:
401:
65:
cells of that organ. The most common stromal cells include
744:"Immunomodulatory properties of mesenchymal stromal cells"
653:
397:
116:
growth and progression. In addition, by regulating local
346:
immune responses. These dendritic cells instead release
1004:
618:
590:
1484:
1329:
1174:
Bernardo, Maria Ester; Fibbe, Willem E. (2013-10-03).
1383:
Mesenchymal
Stromal Cells as Tumor Stromal Modulators
506:
List of human cell types derived from the germ layers
135:
Stromal cells (in the dermis layer) adjacent to the
22:, or mesenchymal stromal cells, are differentiating
1273:Bianco, Paolo; Robey, Pamela Gehron (2000-06-15).
705:"What are Stromal Cells (Mesenchymal Stem Cells)?"
61:. They are cells that support the function of the
1410:
1222:
1539:
793:
1336:Annual Review of Cell and Developmental Biology
742:Nauta, Alma J.; Fibbe, Willem E. (2007-11-15).
1376:
1173:
1080:
1385:, Boston: Academic Press, pp. 103–119,
1470:https://www.youtube.com/watch?v=5xXy7gQjDfg
1272:
523:
430:. Stromal cells also provide nutrients and
295:
224:
81:
1011:Molecular Biology of the Cell. 4th Edition
741:
458:
150:
1518:
1332:"The Biology of Hematopoietic Stem Cells"
1306:
1191:
1114:
1057:
981:
924:
883:
873:
827:
759:
671:
560:
237:. They are located in the stroma and aid
1241:10.1146/annurev.immunol.21.120601.141126
416:
392:. Pathogens are initially recognized by
330:be produced are impacted by diminished
180:. Some stromal cells can be considered
1540:
1023:
1480:
1478:
1279:The Journal of Clinical Investigation
1268:
1266:
1169:
1167:
1165:
673:10.1146/annurev-immunol-032713-120252
851:
849:
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789:
787:
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735:
699:
697:
695:
693:
691:
300:
139:(the top layer of the skin) release
1348:10.1146/annurev.cb.11.110195.000343
1087:International Journal of Stem Cells
486:acute respiratory distress syndrome
374:
16:Connective tissue cell of any organ
13:
1503:10.1097/01.moh.0000245697.54887.6f
1475:
1263:
1162:
14:
1564:
1024:Zhou, Haibo; Wu, Li (July 2017).
844:
784:
732:
688:
264:
112:is known to play a major role in
160:(MSC). It is non-hematopoietic,
1462:
1404:
1370:
1323:
1216:
1153:
1143:
1139:https://doi.org/10.1038/nri3209
1131:
1074:
1017:
998:
949:
900:
524:Wiseman BS, Werb Z (May 2002).
277:Certain types of skin cancers (
722:
647:
612:
584:
517:
156:specifically referred to as a
1:
1491:Current Opinion in Hematology
511:
926:10.1097/JTO.0b013e3181f8a1bd
913:Journal of Thoracic Oncology
761:10.1182/blood-2007-02-069716
132:and inflammatory processes.
97:
7:
1487:"Mesenchymal Stromal Cells"
1421:10.1101/2020.04.13.20064162
1275:"Marrow stromal stem cells"
1229:Annual Review of Immunology
660:Annual Review of Immunology
499:
353:indoleamine 2,3-dioxygenase
10:
1569:
1193:10.1016/j.stem.2013.09.006
1007:"T Cells and MHC Proteins"
480:as well as wound healing,
257:and fluid, as well as the
90:
1099:10.15283/ijsc.2009.2.1.59
1042:10.1007/s13238-017-0398-2
875:10.1186/s13058-016-0740-2
594:European Cytokine Network
453:Multipotent stromal cells
296:Immunomodulatory effects
225:Sources of stromal cells
205:. They can also display
158:mesenchymal stromal cell
1548:Connective tissue cells
553:10.1126/science.1067431
459:Use in future therapies
443:Stroma (disambiguation)
191:human leukocyte antigen
151:Defining a stromal cell
1450:Cite journal requires
862:Breast Cancer Research
633:10.1006/cyto.1997.0225
86:, "bed covering", and
82:
417:Role in hematopoiesis
334:count production and
279:basal cell carcinomas
233:until maturation and
219:inflammatory diseases
34:, for example in the
1225:"Toll-Likereceptors"
478:rheumatoid arthritis
470:autoimmune disorders
428:extracellular matrix
323:natural killer cells
187:cell surface markers
812:10.1042/BSR20150025
545:2002Sci...296.1046W
394:toll-like receptors
239:hematopoietic cells
1030:Protein & Cell
800:Bioscience Reports
474:multiple sclerosis
436:adhesion molecules
1392:978-0-12-803102-5
1285:(12): 1663–1668.
962:Nature Immunology
754:(10): 3499–3506.
301:Anti-inflammatory
255:amniotic membrane
253:, dental tissue,
207:anti-inflammatory
170:connective tissue
28:connective tissue
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1291:10.1172/JCI10413
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573:. Archived from
564:
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375:Pro-inflammatory
357:prostaglandin E2
215:immune disorders
178:lymphatic tissue
100:
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448:Stroma of ovary
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315:dendritic cells
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235:differentiation
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211:proinflammatory
153:
120:networks (e.g.
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1180:Cell Stem Cell
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1036:(7): 501–513.
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580:on 2010-06-28.
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265:Role in cancer
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243:adipose tissue
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141:growth factors
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162:multipotent
110:tumor cells
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