Adult stem cell#Intestinal stem cells

A stem cell possesses two properties:

• Self-renewal is the ability to go through numerous cycles of cell division while still maintaining its undifferentiated state. Stem cells can replicate several times and can result in the formation of two stem cells, one stem cell more differentiated than the other, or two differentiated cells.{{Cite web|title=II. What are the unique properties of all stem cells? {{!}} stemcells.nih.gov|url=https://stemcells.nih.gov/info/basics/II.htm|access-date=2021-02-22|website=stemcells.nih.gov}}
• Multipotency or multidifferentiative potential is the ability to generate progeny of several distinct cell types, (for example glial cells and neurons) as opposed to unipotency, which is the term for cells that are restricted to producing a single cell type. However, some researchers do not consider multipotency to be essential and believe that unipotent self-renewing stem cells can exist.{{cite journal | vauthors = Mlsna L |title=Stem Cell Based Treatments and Novel Considerations for Conscience Clause Legislation |journal=Indiana Health Law Review |date=1 January 2011 |volume=8 |issue=2 |doi=10.18060/2020 |oclc=54703225 |doi-access=free }} These properties can be illustrated with relative ease in vitro, using methods such as clonogenic assays, where the progeny of a single cell is characterized. However, it is known that in vitro cell culture conditions can alter the behavior of cells, proving that a particular subpopulation of cells possesses stem cell properties in vivo is challenging, and so considerable debate exists as to whether some proposed stem cell populations in the adult are indeed stem cells.

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter stem cells, whereas asymmetric division produces one stem cell and one progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before finally differentiating into a mature cell. It is believed that the molecular distinction between symmetric and asymmetric divisions lies in the differential segregation of cell membrane proteins (such as receptors) and their associated proteins between the daughter cells.{{cite journal | vauthors = Culurgioni S, Mari S, Bonetti P, Gallini S, Bonetto G, Brennich M, Round A, Nicassio F, Mapelli M | display-authors = 6 | title = Insc:LGN tetramers promote asymmetric divisions of mammary stem cells | journal = Nature Communications | volume = 9 | issue = 1 | pages = 1025 | date = March 2018 | pmid = 29523789 | pmc = 5844954 | doi = 10.1038/s41467-018-03343-4 | bibcode = 2018NatCo...9.1025C }}

Under normal conditions, tissue stem cells divide slowly and infrequently. They exhibit signs of quiescence or reversible growth arrest.{{cite book |doi=10.1007/978-1-4939-7371-2_1 |chapter=Molecular Regulation of Cellular Quiescence: A Perspective from Adult Stem Cells and Its Niches |title=Cellular Quiescence |series=Methods in Molecular Biology |year=2018 | vauthors = So WK, Cheung TH |volume=1686 |pages=1–25 |pmid=29030809 |isbn=978-1-4939-7370-5 }} The niche the stem cell is found in plays a large role in maintaining quiescence. Perturbed niches cause the stem cell to begin actively dividing again to replace lost or damaged cells until the niche is restored. In hematopoietic stem cells, the MAPK/ERK pathway and PI3K/AKT/mTOR pathway regulate this transition.{{cite journal | vauthors = Baumgartner C, Toifl S, Farlik M, Halbritter F, Scheicher R, Fischer I, Sexl V, Bock C, Baccarini M | display-authors = 6 | title = An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion | journal = Cell Stem Cell | volume = 22 | issue = 6 | pages = 879–892.e6 | date = June 2018 | pmid = 29804890 | pmc = 5988582 | doi = 10.1016/j.stem.2018.05.003 }} The ability to regulate the cell cycle in response to external cues helps prevent stem cell exhaustion or the gradual loss of stem cells following an altered balance between dormant and active states. Infrequent cell divisions also help reduce the risk of acquiring DNA mutations that would be passed on to daughter cells.

Discoveries in recent years have suggested that adult stem cells might have the ability to differentiate into cell types from different germ layers. For instance, neural stem cells from the brain, which are derived from ectoderm, can differentiate into ectoderm, mesoderm, and endoderm.{{cite journal | vauthors = Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlström H, Lendahl U, Frisén J | display-authors = 6 | title = Generalized potential of adult neural stem cells | journal = Science | volume = 288 | issue = 5471 | pages = 1660–1663 | date = June 2000 | pmid = 10834848 | doi = 10.1126/science.288.5471.1660 | bibcode = 2000Sci...288.1660C }} Stem cells from the bone marrow, which is derived from mesoderm, can differentiate into liver, lung, GI tract, and skin, which are derived from endoderm and mesoderm.{{cite journal | vauthors = Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ | display-authors = 6 | title = Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell | journal = Cell | volume = 105 | issue = 3 | pages = 369–377 | date = May 2001 | pmid = 11348593 | doi = 10.1016/s0092-8674(01)00328-2 | s2cid = 11666138 | doi-access = free }} This phenomenon is referred to as stem cell transdifferentiation or plasticity. It can be induced by modifying the growth medium when stem cells are cultured in vitro or by transplanting them to an organ of the body different from the one they were originally isolated from. There is yet no consensus among biologists on the prevalence and physiological and therapeutic relevance of stem cell plasticity. More recent findings suggest that pluripotent stem cells may reside in blood and adult tissues in a dormant state.{{cite journal | vauthors = Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ | title = A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow | journal = Leukemia | volume = 20 | issue = 5 | pages = 857–869 | date = May 2006 | pmid = 16498386 | doi = 10.1038/sj.leu.2404171 | s2cid = 24038471 | doi-access = free }} These cells are referred to as "Blastomere Like Stem Cells" (BLSCs)Am Surg. 2007 Nov; 73: 1106–1110 and "very small embryonic-like" (VSEL) stem cells, and display pluripotency in vitro. As BLSCs and VSEL cells are present in virtually all adult tissues, including the lungs, brain, kidneys, muscles, and pancreas,{{cite journal | vauthors = Zuba-Surma EK, Kucia M, Wu W, Klich I, Lillard JW, Ratajczak J, Ratajczak MZ | title = Very small embryonic-like stem cells are present in adult murine organs: ImageStream-based morphological analysis and distribution studies | journal = Cytometry. Part A | volume = 73A | issue = 12 | pages = 1116–1127 | date = December 2008 | pmid = 18951465 | pmc = 2646009 | doi = 10.1002/cyto.a.20667 }} co-purification of BLSCs and VSEL cells with other populations of adult stem cells may explain the apparent pluripotency of adult stem cell populations. However, recent studies have shown that both human and murine VSEL cells lack stem cell characteristics and are not pluripotent.{{cite journal | vauthors = Danova-Alt R, Heider A, Egger D, Cross M, Alt R | title = Very small embryonic-like stem cells purified from umbilical cord blood lack stem cell characteristics | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e34899 | date = 3 April 2012 | pmid = 22509366 | pmc = 3318011 | doi = 10.1371/journal.pone.0034899 | doi-access = free | bibcode = 2012PLoSO...734899D }}{{cite journal | vauthors = Szade K, Bukowska-Strakova K, Nowak WN, Szade A, Kachamakova-Trojanowska N, Zukowska M, Jozkowicz A, Dulak J | display-authors = 6 | title = Murine bone marrow Lin⁻Sca⁻1⁺CD45⁻ very small embryonic-like (VSEL) cells are heterogeneous population lacking Oct-4A expression | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e63329 | date = 17 May 2013 | pmid = 23696815 | pmc = 3656957 | doi = 10.1371/journal.pone.0063329 | doi-access = free | bibcode = 2013PLoSO...863329S }}{{cite journal | vauthors = Miyanishi M, Mori Y, Seita J, Chen JY, Karten S, Chan CK, Nakauchi H, Weissman IL | display-authors = 6 | title = Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? | journal = Stem Cell Reports | volume = 1 | issue = 2 | pages = 198–208 | date = 6 August 2013 | pmid = 24052953 | pmc = 3757755 | doi = 10.1016/j.stemcr.2013.07.001 }}{{cite journal | vauthors = Miyanishi M, Mori Y, Seita J, Chen JY, Karten S, Chan CK, Nakauchi H, Weissman IL | display-authors = 6 | title = Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? | journal = Stem Cell Reports | volume = 1 | issue = 2 | pages = 198–208 | date = August 2013 | pmid = 24052953 | pmc = 3757755 | doi = 10.1016/j.stemcr.2013.07.001 }}

Stem cell function becomes impaired with age, and this contributes to progressive deterioration of tissue maintenance and repair.{{cite journal | vauthors = Behrens A, van Deursen JM, Rudolph KL, Schumacher B | title = Impact of genomic damage and ageing on stem cell function | journal = Nature Cell Biology | volume = 16 | issue = 3 | pages = 201–207 | date = March 2014 | pmid = 24576896 | pmc = 4214082 | doi = 10.1038/ncb2928 }} A likely important cause of increasing stem cell dysfunction is an age-dependent accumulation of DNA damage in both stem cells and the cells that comprise the stem cell environment. (See also DNA damage theory of aging.)

Adult stem cells can, however, be artificially reverted to a state where they behave like embryonic stem cells (including the associated DNA repair mechanisms). This was done with mice as early as 2006{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–676 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 | hdl-access = free | s2cid = 1565219 | hdl = 2433/159777 | author-link1 = Shinya Yamanaka }} with prospects to slow down human aging substantially.{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–872 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 | hdl-access = free | s2cid = 8531539 | author-link7 = Shinya Yamanaka | hdl = 2433/49782 }} Such cells are one of the various classes of induced stem cells.

Adult stem cell research has been focused on uncovering the general molecular mechanisms that control their self-renewal and differentiation.

• Notch

:The Notch pathway has been known to developmental biologists for decades. Its role in the control of stem cell proliferation has now been demonstrated for several cell types including hematopoietic, neural, and mammary{{cite journal | vauthors = Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS | title = Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells | journal = Breast Cancer Research | volume = 6 | issue = 6 | pages = R605–R615 | date = December 2004 | pmid = 15535842 | pmc = 1064073 | doi = 10.1186/bcr920 | doi-access = free }} stem cells.

• Wnt

:These developmental pathways are also strongly implicated as stem cell regulators.{{cite journal | vauthors = Beachy PA, Karhadkar SS, Berman DM | title = Tissue repair and stem cell renewal in carcinogenesis | journal = Nature | volume = 432 | issue = 7015 | pages = 324–331 | date = November 2004 | pmid = 15549094 | doi = 10.1038/nature03100 | s2cid = 4428056 | bibcode = 2004Natur.432..324B }}

• TGFβ

:The TGFβ family of cytokines regulate the stemness of both normal and cancer stem cells.{{cite journal | vauthors = Sakaki-Yumoto M, Katsuno Y, Derynck R | title = TGF-β family signaling in stem cells | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1830 | issue = 2 | pages = 2280–2296 | date = February 2013 | pmid = 22959078 | pmc = 4240309 | doi = 10.1016/j.bbagen.2012.08.008 }}

{{main|Hematopoietic stem cell}}

Hematopoietic stem cells (HSCs) are stem cells that can differentiate into all blood cells.{{cite journal | vauthors = Birbrair A, Frenette PS | title = Niche heterogeneity in the bone marrow | journal = Annals of the New York Academy of Sciences | volume = 1370 | issue = 1 | pages = 82–96 | date = April 2016 | pmid = 27015419 | pmc = 4938003 | doi = 10.1111/nyas.13016 | bibcode = 2016NYASA1370...82B }} This process is called hematopoiesis.{{Cite web|url=https://www.medicinenet.com/script/main/art.asp?articlekey=19775.|title=Medical Definition of Hematopoiesis|website=MedicineNet|url-status=dead|archive-url=https://web.archive.org/web/20170314194407/https://www.medicinenet.com/script/main/art.asp?articlekey=19775|archive-date=2017-03-14|access-date=2020-02-21}} Hematopoietic stem cells are found in the bone marrow and umbilical cord blood.{{Cite web|url=http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx|title=5. Hematopoietic Stem Cells [Stem Cell Information]|date=2001-06-17|website=stemcells.nih.gov|url-status=dead|archive-url=https://web.archive.org/web/20140605205207/http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx|archive-date=2014-06-05|access-date=2020-02-21}} The HSCs are generally dormant when found in adults due to their nature.{{cite journal | vauthors = Srikanth L, Sunitha MM, Venkatesh K, Kumar PS, Chandrasekhar C, Vengamma B, Sarma PV | title = Anaerobic Glycolysis and HIF1α Expression in Haematopoietic Stem Cells Explains Its Quiescence Nature | journal = Journal of Stem Cells | volume = 10 | issue = 2 | pages = 97–106 | date = 2015 | pmid = 27125138 | id = {{ProQuest|1769944207}} }}

{{See also|Breast cancer stem cell}}

Mammary stem cells provide the source of cells for the growth of the mammary gland during puberty and gestation and play an important role in the carcinogenesis of the breast.{{cite journal | vauthors = Liu S, Dontu G, Wicha MS | title = Mammary stem cells, self-renewal pathways, and carcinogenesis | journal = Breast Cancer Research | volume = 7 | issue = 3 | pages = 86–95 | date = June 2005 | pmid = 15987436 | pmc = 1143566 | doi = 10.1186/bcr1021 | doi-access = free }} Mammary stem cells have been isolated from human and mouse tissue as well as from cell lines derived from the mammary gland. Single such cells can give rise to both the luminal and myoepithelial cell types of the gland and have been shown to have the ability to regenerate the entire organ in mice.

{{Main|Intestinal gland}}

Intestinal stem cells divide continuously throughout life and use a complex genetic program to produce the cells lining the surface of the small and large intestines.{{cite journal | vauthors = van der Flier LG, Clevers H | title = Stem cells, self-renewal, and differentiation in the intestinal epithelium | journal = Annual Review of Physiology | volume = 71 | issue = 1 | pages = 241–260 | date = March 2009 | pmid = 18808327 | doi = 10.1146/annurev.physiol.010908.163145 }} Intestinal stem cells reside near the base of the stem cell niche, called the crypts of Lieberkuhn. Intestinal stem cells are probably the source of most cancers of the small intestine and colon.{{cite journal | vauthors = Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H | display-authors = 6 | title = Crypt stem cells as the cells-of-origin of intestinal cancer | journal = Nature | volume = 457 | issue = 7229 | pages = 608–611 | date = January 2009 | pmid = 19092804 | doi = 10.1038/nature07602 | s2cid = 4422868 | bibcode = 2009Natur.457..608B }}

{{main|Mesenchymal stem cell}}

Mesenchymal stem cells (MSCs) are of stromal origin and may differentiate into a variety of tissues. MSCs have been isolated from the placenta, adipose tissue, lung, bone marrow and blood, Wharton's jelly from the umbilical cord, and teeth (perivascular niche of dental pulp and periodontal ligament).{{cite journal | vauthors = Shi S, Bartold PM, Miura M, Seo BM, Robey PG, Gronthos S | title = The efficacy of mesenchymal stem cells to regenerate and repair dental structures | journal = Orthodontics & Craniofacial Research | volume = 8 | issue = 3 | pages = 191–199 | date = August 2005 | pmid = 16022721 | doi = 10.1111/j.1601-6343.2005.00331.x | citeseerx = 10.1.1.456.7504 }} MSCs are attractive for clinical therapy due to their ability to differentiate, provide trophic support, and modulate innate immune response.{{cite journal | vauthors = Phinney DG, Prockop DJ | title = Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair--current views | journal = Stem Cells | volume = 25 | issue = 11 | pages = 2896–2902 | date = November 2007 | pmid = 17901396 | doi = 10.1634/stemcells.2007-0637 | s2cid = 1352725 | doi-access = free }} These cells differentiate into various cell types such as osteoblasts, chondroblasts, adipocytes, neuroectodermal cells, and hepatocytes.{{cite journal | vauthors = Bai X, Alt E | title = Myocardial regeneration potential of adipose tissue-derived stem cells | journal = Biochemical and Biophysical Research Communications | volume = 401 | issue = 3 | pages = 321–326 | date = October 2010 | pmid = 20833143 | doi = 10.1016/j.bbrc.2010.09.012 }} Bioactive mediators that favor local cell growth are also secreted by MSCs. Anti-inflammatory effects on the local microenvironment, which promote tissue healing, are also observed. The inflammatory response can be modulated by adipose-derived regenerative cells (ADRC) including mesenchymal stem cells and regulatory T-lymphocytes. The mesenchymal stem cells thus alter the outcome of the immune response by changing the cytokine secretion of dendritic and T-cell subsets. This results in a shift from a pro-inflammatory environment to an anti-inflammatory or tolerant cell environment.{{cite journal | vauthors = Aggarwal S, Pittenger MF | title = Human mesenchymal stem cells modulate allogeneic immune cell responses | journal = Blood | volume = 105 | issue = 4 | pages = 1815–1822 | date = February 2005 | pmid = 15494428 | doi = 10.1182/blood-2004-04-1559 | doi-access = free }}{{cite journal | vauthors = Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G | title = Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis | journal = Arthritis and Rheumatism | volume = 56 | issue = 4 | pages = 1175–1186 | date = April 2007 | pmid = 17393437 | doi = 10.1002/art.22511 | doi-access = free }}

{{main|Endothelial stem cell}}

Endothelial stem cells are one of the three types of multipotent stem cells found in the bone marrow. They are a rare and controversial group with the ability to differentiate into endothelial cells, the cells that line blood vessels as well as lymphatic vessels. Endothelial stem cells are an important aspect of the vascular network, even influencing the motion relating to white blood cells.

{{main|Neural stem cell}}

The existence of stem cells in the adult brain has been postulated following the discovery that the process of neurogenesis, the birth of new neurons, continues into adulthood in rats.{{cite journal | vauthors = Altman J, Das GD | title = Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats | journal = The Journal of Comparative Neurology | volume = 124 | issue = 3 | pages = 319–335 | date = June 1965 | pmid = 5861717 | doi = 10.1002/cne.901240303 | s2cid = 14121873 }} The presence of stem cells in the mature primate brain was first reported in 1967.{{cite journal | vauthors = Lewis PD | title = Mitotic activity in the primate subependymal layer and the genesis of gliomas | journal = Nature | volume = 217 | issue = 5132 | pages = 974–975 | date = March 1968 | pmid = 4966809 | doi = 10.1038/217974a0 | s2cid = 4169368 | bibcode = 1968Natur.217..974L }} It has since been shown that new neurons are generated in adult mice, songbirds, and primates, including humans. Normally, adult neurogenesis is restricted to two areas of the brain – the subventricular zone, which lines the lateral ventricles, and the dentate gyrus of the hippocampal formation.{{cite journal | vauthors = Alvarez-Buylla A, Seri B, Doetsch F | title = Identification of neural stem cells in the adult vertebrate brain | journal = Brain Research Bulletin | volume = 57 | issue = 6 | pages = 751–758 | date = April 2002 | pmid = 12031271 | doi = 10.1016/s0361-9230(01)00770-5 | s2cid = 40684602 }} Although the generation of new neurons in the hippocampus is well established, the presence of true self-renewing stem cells there has been debated.{{cite journal | vauthors = Bull ND, Bartlett PF | title = The adult mouse hippocampal progenitor is neurogenic but not a stem cell | journal = The Journal of Neuroscience | volume = 25 | issue = 47 | pages = 10815–10821 | date = November 2005 | pmid = 16306394 | pmc = 6725873 | doi = 10.1523/JNEUROSCI.3249-05.2005 }} Under certain circumstances, such as following tissue damage in ischemia, neurogenesis can be induced in other brain regions, including the neocortex.

Neural stem cells are commonly cultured in vitro as so-called neurospheres – floating heterogeneous aggregates of cells, containing a large proportion of stem cells.{{cite journal | vauthors = Reynolds BA, Weiss S | title = Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system | journal = Science | volume = 255 | issue = 5052 | pages = 1707–1710 | date = March 1992 | pmid = 1553558 | doi = 10.1126/science.1553558 | bibcode = 1992Sci...255.1707R }} They can be propagated for extended periods and differentiated into both neuronal and glial cells, and therefore behave as stem cells. However, some recent studies suggest that this behavior is induced by the culture conditions in progenitor cells, the progeny of stem cell division that normally undergo a strictly limited number of replication cycles in vivo.{{cite journal | vauthors = Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A | title = EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells | journal = Neuron | volume = 36 | issue = 6 | pages = 1021–1034 | date = December 2002 | pmid = 12495619 | doi = 10.1016/s0896-6273(02)01133-9 | s2cid = 3250093 | doi-access = free }} Furthermore, neurosphere-derived cells do not behave as stem cells when transplanted back into the brain.{{cite journal | vauthors = Marshall GP, Laywell ED, Zheng T, Steindler DA, Scott EW | title = In vitro-derived "neural stem cells" function as neural progenitors without the capacity for self-renewal | journal = Stem Cells | volume = 24 | issue = 3 | pages = 731–738 | date = March 2006 | pmid = 16339644 | doi = 10.1634/stemcells.2005-0245 | s2cid = 25223188 | doi-access = free }}

Neural stem cells share many properties with hematopoietic stem cells (HSCs). Remarkably, when injected into the blood, neurosphere-derived cells differentiate into various cell types of the immune system.{{cite journal | vauthors = Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL | title = Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo | journal = Science | volume = 283 | issue = 5401 | pages = 534–537 | date = January 1999 | pmid = 9915700 | doi = 10.1126/science.283.5401.534 | bibcode = 1999Sci...283..534B }}

{{See also|Stratum basale}}

Olfactory adult stem cells have been successfully harvested from the human olfactory mucosa cells, which are found in the lining of the nose and are involved in the sense of smell.{{cite journal | vauthors = Murrell W, Féron F, Wetzig A, Cameron N, Splatt K, Bellette B, Bianco J, Perry C, Lee G, Mackay-Sim A | display-authors = 6 | title = Multipotent stem cells from adult olfactory mucosa | journal = Developmental Dynamics | volume = 233 | issue = 2 | pages = 496–515 | date = June 2005 | pmid = 15782416 | doi = 10.1002/dvdy.20360 | name-list-style = vanc | s2cid = 38561781 | doi-access = free }} If they are given the right chemical environment, these cells have the same ability as embryonic stem cells to develop into many different cell types. Olfactory stem cells hold the potential for therapeutic applications and, in contrast to neural stem cells, can be harvested with ease without harm to the patient. This means they can be easily obtained from all individuals, including older patients who might be most in need of stem cell therapies.

{{See also|Neural crest}}

Hair follicles contain two types of stem cells, one of which appears to represent a remnant of the stem cells of the embryonic neural crest. Similar cells have been found in the gastrointestinal tract, sciatic nerve, cardiac outflow tract and spinal and sympathetic ganglia. These cells can generate neurons, Schwann cells, myofibroblasts, chondrocytes, and melanocytes.{{cite journal | vauthors = Sieber-Blum M, Hu Y | title = Epidermal neural crest stem cells (EPI-NCSC) and pluripotency | journal = Stem Cell Reviews | volume = 4 | issue = 4 | pages = 256–260 | date = December 2008 | pmid = 18712509 | doi = 10.1007/s12015-008-9042-0 | s2cid = 23267408 }}{{cite journal | vauthors = Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ | title = Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness | journal = Neuron | volume = 35 | issue = 4 | pages = 657–669 | date = August 2002 | pmid = 12194866 | pmc = 2728576 | doi = 10.1016/s0896-6273(02)00827-9 }}

{{See also|Germ cell|Spermatogonial stem cell}}

Multipotent stem cells with a claimed equivalency to embryonic stem cells have been derived from spermatogonial progenitor cells found in the testicles of laboratory mice by scientists in Germany{{cite news |title=Testicle cells may aid research |url=http://news.bbc.co.uk/2/hi/health/4841786.stm |date=25 March 2006 }}{{cite news |title=Study: Mice Testes Act Like Stem Cells |url=https://www.cbsnews.com/news/study-mice-testes-act-like-stem-cells/ |work=CBS News |agency=Associated Press |date=24 March 2006 }}{{cite news|url=https://www.washingtonpost.com/wp-dyn/content/article/2006/03/24/AR2006032401721.html|newspaper=Washington Post|date=25 March 2006|title=Embryonic Stem Cell Success| vauthors = Weiss R }} and the United States,{{cite web|url=https://www.sciencedaily.com/releases/2007/09/070919131804.htm|work=Science Daily|title=Promising New Source of Stem Cells: Mouse Testes Produce Wide Range of Tissue Types|date=24 September 2007}}{{cite news|title=Testicles yield stem cells in science breakthrough|url=http://abc.net.au/news/stories/2007/09/20/2039030.htm?section=world|archive-url=https://web.archive.org/web/20071011085454/http://abc.net.au/news/stories/2007/09/20/2039030.htm?section=world|url-status=dead|archive-date=11 October 2007| vauthors = Miller B |newspaper = ABC News|date=20 September 2007|publisher=Australian Broadcasting Corporation}}{{cite web|url=http://www.sciam.com/article.cfm?articleID=1F52615A-E7F2-99DF-3EB290B3C5A45982|work=Scientific American|title=Testes May Prove Fertile Source of Stem Cells| vauthors = Minkel JR |date=19 September 2007}}{{cite web|url=http://news.med.cornell.edu/wcmc/wcmc_2007/09_20_07-2.shtml|title=Stem Cells in Adult Testes Provide Alternative to Embryonic Stem Cells for Organ Regeneration|publisher=Cornell University|date=20 September 2007}} and, a year later, researchers from Germany and the United Kingdom confirmed the same capability using cells from the testicles of humans.{{cite web|url=https://www.bloomberg.com/apps/news?pid=20601124&sid=aNmiXs8SPp4w&refer=home|date=8 October 2008|title=Testicle Stem Cells Become Bone, Muscle in German Experiments | vauthors = Waters R |publisher=Bloomberg News}} The extracted stem cells are known as human adult germline stem cells (GSCs){{cite web|url=http://www.technologyreview.com/biomedicine/21487/|title=A Source of Men's Stem Cells – Stem cells from human testes could be used for personalized medicine | vauthors = Schultz N |date=9 October 2008|work=Technology Review}}

Multipotent stem cells have also been derived from germ cells found in human testicles.{{cite news|url=https://www.washingtonpost.com/wp-dyn/content/article/2006/04/01/AR2006040101145.html|title=U.S. Firm Says It Made Stem Cells From Human Testes| vauthors = Fox M | agency = Reuters |newspaper=Washington Post|date=2 April 2006}}

Adult stem cell treatments have been used for many years to successfully treat leukemia and related bone/blood cancers utilizing bone marrow transplants.[http://www.ucsfhealth.org/childrens/medical_services/cancer/bmt/treatments/leukemia.html Bone Marrow Transplant] Retrieved on 21 November 2008 The use of adult stem cells in research and therapy is not considered as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo.

Early regenerative applications of adult stem cells have focused on intravenous delivery of blood progenitors known as Hematopoietic Stem Cells (HSCs). CD34+ hematopoietic Stem Cells have been clinically applied to treat various diseases including spinal cord injury,{{cite journal | vauthors = Srivastava A, Bapat M, Ranade S, Srinivasan V, Murugan P, Manjunath S, Thamaraikannan P, Abraham S | display-authors = 6 | title = Multiple injections of in vitro expanded autologous bone marrow stem cells for cervical level spinal cord injury – a case report | journal = Journal of Stem Cells & Regenerative Medicine | volume = 6 | issue = 3 | pages = 175–176 | date = 2010 | pmid = 24693165 }} liver cirrhosis{{cite journal | vauthors = Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I | display-authors = 6 | title = Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy | journal = Stem Cells | volume = 24 | issue = 10 | pages = 2292–2298 | date = October 2006 | pmid = 16778155 | doi = 10.1634/stemcells.2005-0542 | s2cid = 5649484 }} and Peripheral Vascular disease.{{cite journal | vauthors = Subrammaniyan R, Amalorpavanathan J, Shankar R, Rajkumar M, Baskar S, Manjunath SR, Senthilkumar R, Murugan P, Srinivasan VR, Abraham S | display-authors = 6 | title = Application of autologous bone marrow mononuclear cells in six patients with advanced chronic critical limb ischemia as a result of diabetes: our experience | journal = Cytotherapy | volume = 13 | issue = 8 | pages = 993–999 | date = September 2011 | pmid = 21671823 | doi = 10.3109/14653249.2011.579961 | s2cid = 27251276 }} Research has shown that CD34+ hematopoietic Stem Cells are relatively more numerous in men than in women of reproductive age group among spinal cord Injury victims.{{cite journal | vauthors = Dedeepiya VD, Rao YY, Jayakrishnan GA, Parthiban JK, Baskar S, Manjunath SR, Senthilkumar R, Abraham SJ | display-authors = 6 | title = Index of CD34+ Cells and Mononuclear Cells in the Bone Marrow of Spinal Cord Injury Patients of Different Age Groups: A Comparative Analysis | journal = Bone Marrow Research | volume = 2012 | pages = 787414 | date = 5 July 2012 | pmid = 22830032 | pmc = 3398573 | doi = 10.1155/2012/787414 | doi-access = free }} Other early commercial applications have focused on Mesenchymal Stem Cells (MSCs). For both cell lines, direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenously injected cells are sequestered in the lungs.{{cite journal | vauthors = Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS | display-authors = 6 | title = Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect | journal = Stem Cells and Development | volume = 18 | issue = 5 | pages = 683–692 | date = June 2009 | pmid = 19099374 | pmc = 3190292 | doi = 10.1089/scd.2008.0253 }} Clinical case reports in orthopedic applications have been published. Wakitani has published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.{{cite journal | vauthors = Wakitani S, Nawata M, Tensho K, Okabe T, Machida H, Ohgushi H | title = Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees | journal = Journal of Tissue Engineering and Regenerative Medicine | volume = 1 | issue = 1 | pages = 74–79 | date = January 2007 | pmid = 18038395 | doi = 10.1002/term.8 | s2cid = 24093117 | doi-access = free }} Centeno et al. have reported high-field MRI evidence of increased cartilage and meniscus volume in individual human clinical subjects as well as a large n=227 safety study.{{cite journal | vauthors = Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D | title = Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells | journal = Medical Hypotheses | volume = 71 | issue = 6 | pages = 900–908 | date = December 2008 | pmid = 18786777 | doi = 10.1016/j.mehy.2008.06.042 }}{{cite journal | vauthors = Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D | title = Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells | journal = Pain Physician | volume = 11 | issue = 3 | pages = 343–353 | date = May 2008 | pmid = 18523506 | url = http://www.painphysicianjournal.com/linkout?issn=1533-3159&vol=11&page=343 }}{{cite journal | vauthors = Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W | title = Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique | journal = Current Stem Cell Research & Therapy | volume = 5 | issue = 1 | pages = 81–93 | date = March 2010 | pmid = 19951252 | doi = 10.2174/157488810790442796 }} Many other stem cell-based treatments are operating outside the US, with much controversy being reported regarding these treatments as some feel more regulation is needed as clinics tend to exaggerate claims of success and minimize or omit risks.{{cite press release |title=The ISSCR Releases New Guidelines to Shape Future of Stem Cell Therapy |publisher=International Society for Stem Cell Research |date=3 December 2008 |url=https://www.isscr.org/news-publicationsss/isscr-news-articles/article-listing/2008/12/04/the-isscr-releases-new-guidelines-to-shape-future-of-stem-cell-therapy }}

{{main|Stem cell therapy}}

The therapeutic potential of adult stem cells is the focus of much scientific research, due to their ability to be harvested from the parent body that is females during the delivery.{{cite journal | vauthors = Liao YH, Verchere CB, Warnock GL | title = Adult stem or progenitor cells in treatment for type 1 diabetes: current progress | journal = Canadian Journal of Surgery. Journal Canadien de Chirurgie | volume = 50 | issue = 2 | pages = 137–142 | date = April 2007 | pmid = 17550719 | pmc = 2384257 }}{{cite journal | vauthors = Mimeault M, Hauke R, Batra SK | title = Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies | journal = Clinical Pharmacology and Therapeutics | volume = 82 | issue = 3 | pages = 252–264 | date = September 2007 | pmid = 17671448 | doi = 10.1038/sj.clpt.6100301 | s2cid = 12411918 }}{{cite journal | vauthors = Christoforou N, Gearhart JD | title = Stem cells and their potential in cell-based cardiac therapies | journal = Progress in Cardiovascular Diseases | volume = 49 | issue = 6 | pages = 396–413 | date = May 2007 | pmid = 17498520 | doi = 10.1016/j.pcad.2007.02.006 }} In common with embryonic stem cells, adult stem cells can differentiate into more than one cell type, but unlike the former they are often restricted to certain types or "lineages". The ability of a differentiated stem cell of one lineage to produce cells of a different lineage is called transdifferentiation. Some types of adult stem cells are more capable of transdifferentiation than others, but for many there is no evidence that such a transformation is possible. Consequently, adult stem therapies require a stem cell source of the specific lineage needed, and harvesting and/or culturing them up to the numbers required is a challenge.{{cite journal | vauthors = Raff M | title = Adult stem cell plasticity: fact or artifact? | journal = Annual Review of Cell and Developmental Biology | volume = 19 | issue = 1 | pages = 1–22 | date = November 2003 | pmid = 14570561 | doi = 10.1146/annurev.cellbio.19.111301.143037 }}{{cite journal | vauthors = Smith S, Neaves W, Teitelbaum S | title = Adult versus embryonic stem cells: treatments | journal = Science | volume = 316 | issue = 5830 | pages = 1422–1423; author reply 1422–1423 | date = June 2007 | pmid = 17556566 | doi = 10.1126/science.316.5830.1422b | s2cid = 12738214 }} Additionally, cues from the immediate environment (including how stiff or porous the surrounding structure/extracellular matrix is) can alter or enhance the fate and differentiation of the stem cells.{{cite journal | vauthors = Huang C, Dai J, Zhang XA | title = Environmental physical cues determine the lineage specification of mesenchymal stem cells | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1850 | issue = 6 | pages = 1261–1266 | date = June 2015 | pmid = 25727396 | pmc = 4411082 | doi = 10.1016/j.bbagen.2015.02.011 }}

Pluripotent stem cells, i.e. cells that can give rise to any fetal or adult cell type, can be found in several tissues, including umbilical cord blood.{{cite journal | vauthors = Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M | title = A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues | journal = Leukemia | volume = 21 | issue = 5 | pages = 860–867 | date = May 2007 | pmid = 17344915 | doi = 10.1038/sj.leu.2404630 | doi-access = free }} Using genetic reprogramming, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.{{cite news|title=Me too, too – How to make human embryonic stem cells without destroying human embryos|newspaper=The Economist|url=http://www.economist.com/science/displaystory.cfm?story_id=10170972|date=22 November 2007}}{{cite news | vauthors = Kolata G |title=Scientists Bypass Need for Embryo to Get Stem Cells |url=https://www.nytimes.com/2007/11/21/science/21stem.html |work=The New York Times |date=21 November 2007 }}{{cite web|url=https://www.theglobeandmail.com/servlet/story/RTGAM.20071121.wstemcells21/BNStory/Science/home|title=Stem-cell method hailed as 'massive breakthrough'| vauthors = McIlroy A |date=21 November 2007|work=Globe and Mail |location=Canada }}{{cite magazine|title=A Breakthrough on Stem Cells|magazine=Time |url=http://www.time.com/time/health/article/0,8599,1685965,00.html|archive-url=https://web.archive.org/web/20071121112718/http://www.time.com/time/health/article/0,8599,1685965,00.html|url-status=dead|archive-date=21 November 2007| vauthors = Park A |date=20 November 2007}} Other adult stem cells are multipotent, meaning there are several limited types of cell they can become, and are generally referred to by their tissue origin (such as mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).{{cite journal | vauthors = Barrilleaux B, Phinney DG, Prockop DJ, O'Connor KC | title = Review: ex vivo engineering of living tissues with adult stem cells | journal = Tissue Engineering | volume = 12 | issue = 11 | pages = 3007–3019 | date = November 2006 | pmid = 17518617 | doi = 10.1089/ten.2006.12.3007 }}{{cite journal | vauthors = Gimble JM, Katz AJ, Bunnell BA | title = Adipose-derived stem cells for regenerative medicine | journal = Circulation Research | volume = 100 | issue = 9 | pages = 1249–1260 | date = May 2007 | pmid = 17495232 | pmc = 5679280 | doi = 10.1161/01.RES.0000265074.83288.09 }} A great deal of adult stem cell research has focused on investigating their capacity to divide or self-renew indefinitely, and their differentiation potential.{{cite journal | vauthors = Gardner RL | title = Stem cells: potency, plasticity and public perception | journal = Journal of Anatomy | volume = 200 | issue = Pt 3 | pages = 277–282 | date = March 2002 | pmid = 12033732 | pmc = 1570679 | doi = 10.1046/j.1469-7580.2002.00029.x }} In mice, pluripotent stem cells can be directly generated from adult fibroblast cultures.{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–676 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 | hdl-access = free | s2cid = 1565219 | hdl = 2433/159777 }}

In recent years, acceptance of the concept of adult stem cells has increased. There is now a hypothesis that stem cells reside in many adult tissues and that these unique reservoirs of cells not only are responsible for the normal reparative and regenerative processes but are also considered to be a prime target for genetic and epigenetic changes, culminating in many abnormal conditions including cancer.{{cite journal | vauthors = Presnell SC, Petersen B, Heidaran M | title = Stem cells in adult tissues | journal = Seminars in Cell & Developmental Biology | volume = 13 | issue = 5 | pages = 369–376 | date = October 2002 | pmid = 12324219 | doi = 10.1016/s1084952102000939 }}{{cite journal | vauthors = Cogle CR, Guthrie SM, Sanders RC, Allen WL, Scott EW, Petersen BE | title = An overview of stem cell research and regulatory issues | journal = Mayo Clinic Proceedings | volume = 78 | issue = 8 | pages = 993–1003 | date = August 2003 | pmid = 12911047 | doi = 10.4065/78.8.993 | doi-access = free }} (See cancer stem cell for more details.)

Adult stem cells express transporters of the ATP-binding cassette family that actively pump a diversity of organic molecules out of the cell.{{cite journal | vauthors = Chaudhary PM, Roninson IB | title = Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells | journal = Cell | volume = 66 | issue = 1 | pages = 85–94 | date = July 1991 | pmid = 1712673 | doi = 10.1016/0092-8674(91)90141-k | s2cid = 1717379 }} Many pharmaceuticals are exported by these transporters conferring multidrug resistance onto the cell. This complicates the design of drugs, for instance, neural stem cell-targeted therapies for the treatment of clinical depression.

The virus that causes COVID-19, SARS-CoV-2, damages the lungs extensively in the presence of an overreactive immune response. Adult stem cells were extracted from deep lung biopsies and used to construct a complete lung model with both proximal and distal airway epithelia. After being developed in 3D cultures, the organoids were separated into individual cells to form 2D monolayers. These lung models were used to study the damage SARS-CoV-2 causes when applied to the apical side of the transwell.{{cite journal | vauthors = Tindle C, Fuller M, Fonseca A, Taheri S, Ibeawuchi SR, Beutler N, Katkar GD, Claire A, Castillo V, Hernandez M, Russo H, Duran J, Crotty Alexander LE, Tipps A, Lin G, Thistlethwaite PA, Chattopadhyay R, Rogers TF, Sahoo D, Ghosh P, Das S | display-authors = 6 | title = Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19 | journal = eLife | volume = 10 | pages = e66417 | date = August 2021 | pmid = 34463615 | pmc = 8463074 | doi = 10.7554/eLife.66417 | veditors = Radisic M, Van der Meer JW, Clevers H | doi-access = free }}

Due to their multipotency, capacity to release growth factors, and immunomodulatory abilities, stem cell-based therapies have become a viable tool for the treatment of both acute and delayed phases of stroke. By inducing neurogenesis, angiogenesis, and synaptogenesis as well as activating endogenous restorative processes through the generation of cytokines and trophic factors, this transdifferentiation can form cells with a neural lineage.{{cite journal | vauthors = Fernández-Susavila H, Bugallo-Casal A, Castillo J, Campos F | title = Adult Stem Cells and Induced Pluripotent Stem Cells for Stroke Treatment | journal = Frontiers in Neurology | volume = 10 | pages = 908 | date = 2019 | pmid = 31555195 | pmc = 6722184 | doi = 10.3389/fneur.2019.00908 | doi-access = free }}

• Induced somatic stem cells

{{Reflist}}

• [http://stemcells.nih.gov/ NIH Stem Cell Information Resource], a resource for stem cell research
• [http://www.nature.com/stemcells Nature Reports Stem Cells] Background information, research advances, and debates about stem cell science
• [https://web.archive.org/web/20060708052521/http://www.umdnj.edu/gsbsnweb/stemcell/ UMDNJ Stem Cell and Regenerative Medicine] provides educational materials and research resources
• [http://www.hopkinsmedicine.org/stem_cell_research Stem Cell Research at Johns Hopkins University]

{{Stem cells}}

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{{DEFAULTSORT:Adult Stem Cell}}

Category:Stem cells

Category:Biotechnology