Biomedical subjects

Richard Poulsom

Publications and source records attributed to Richard Poulsom.

At least 19 recordsLinked to original sources

PubMed2003

EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor.

We have identified a novel protein-disulfide isomerase and named it endothelial protein-disulfide isomerase (EndoPDI) because of its high expression in endothelial cells. Isolation of the full-length cDNA showed EndoPDI to be a 48 kDa protein that has three APWCGHC thioredoxin motifs in contrast to the two present in archetypal PDI. Ribonuclease protection and Western analysis has shown that hypoxia induces EndoPDI mRNA and protein expression. In situ hybridization analysis showed that EndoPDI expression is rare in normal tissues, except for keratinocytes of the hair bulb and syncytiotrophoblasts of the placenta, but was present in the endothelium of tumors and in other hypoxic lesions such as atherosclerotic plaques. We have compared the function of EndoPDI to that of PDI in endothelial cells using specific siRNA. PDI was shown to have a protective effect on endothelial cells under both normoxia and hypoxia. In contrast, EndoPDI has a protective effect only in endothelial cells exposed to hypoxia. The loss of EndoPDI expression under hypoxia caused a significant decrease in the secretion of adrenomedullin, endothelin-1, and CD105; molecules that protect endothelial cells from hypoxia-initiated apoptosis. The identification of an endothelial PDI further extends this increasing multigene family and EndoPDI, unlike archetypal PDI, may be a molecule with which to target tumor endothelium.

Amino Acid Motifs↗

PubMed2003

Bottom-up histogenesis of colorectal adenomas: origin in the monocryptal adenoma and initial expansion by crypt fission.

The adenoma:carcinoma sequence is well established. Understanding the molecular pathology of the adenoma is therefore important. There is great controversy within the field. The Vogelstein group champions the "top-down" theory (colorectal adenomas arise and grow across the mucosal surface and down into the crypts), whereas other studies, including our own, propose "bottom-up" spread. Serial sections of 40 small (<3 mm) sporadic colorectal adenomas were stained with H&E, MIB-1, and for beta-catenin. 10 early adenomas were Feulgen-stained and microdissected. We also examined the flat mucosa of three patients who had undergone colectomies for familial adenomatous polyposis (FAP) and specimens from a XO/XY individual with FAP, the latter using in situ hybridization for the Y chromosome. In the earliest sporadic adenomas, there were crypts entirely filled with adenomatous epithelium, which showed proliferative activity and nuclear localization of beta-catenin. There was a sharp cutoff between crypt epithelial cells showing nuclear beta-catenin and surface cells with membrane staining. In slightly larger lesions, adenomatous spread from above was seen. Microdissected adenomas showed multiple fission events, with proliferation distributed equally throughout. In FAP tissue, numerous isolated monocryptal adenomas, which were clonal in origin, were seen. Examination of adenomas in the XO/XY individual showed no instances of XY or XO adenomatous epithelium growing down into crypts of the other genotype. Both sporadic and FAP adenomas start as a unicryptal adenomas and grow initially by crypt fission--a bottom-up pattern. Later, in sporadic adenomas, there is evidence of growth down into adjacent crypts (top-down).

Adenoma↗

PubMed2003

A novel and highly conserved collagen (pro(alpha)1(XXVII)) with a unique expression pattern and unusual molecular characteristics establishes a new clade within the vertebrate fibrillar collagen family.

The type XXVII collagen gene codes for a novel vertebrate fibrillar collagen that is highly conserved in man, mouse, and fish (Fugu rubripes). The pro(alpha)1(XXVII) chain has a domain structure similar to that of the type B clade chains (alpha1(V), alpha3(V), alpha1(XI), and alpha2(XI)). However, compared with other vertebrate fibrillar collagens (types I, II, III, V, and XI), type XXVII collagen has unusual molecular features such as no minor helical domain, a major helical domain that is short and interrupted, and a short chain selection sequence within the NC1 domain. Pro(alpha)1(XXVII) mRNA is 9 kb and expressed by chondrocytes but also by a variety of epithelial cell layers in developing tissues including stomach, lung, gonad, skin, cochlear, and tooth. By Western blotting, type XXVII antisera recognized multiple bands of 240-110 kDa in tissue extracts and collagenous bands of 150-140 kDa in the conditioned medium of the differentiating chondrogenic ATDC5 cell line. Phylogenetic analyses revealed that type XXVII, together with the closely related type XXIV collagen gene, form a new, third clade (type C) within the vertebrate fibrillar collagen family. Furthermore, the exon structure of the type XXVII collagen gene is similar to, but distinct from, those of the genes coding for the type A or B clade pro(alpha) chains.

Amino Acid Sequence↗

PubMed2003

A study of regional gut endoderm potency by analysis of Cdx2 null mutant chimaeric mice.

Inactivation of Cdx2 by homologous recombination results in the development of forestomach epithelium at ectopic sites in pericaecal areas of the midgut of heterozygote mice. Local factors subsequently result in the secondary induction of tissues exhibiting an orderly sequence of tissue types between the ectopic forestomach tissue and the surrounding colon. Clonal analysis of this secondarily generated tissue using Y chromosome painting in chimaeric mice indicates that once differentiated to express Cdx2, host colonic epithelium can only form small intestinal-type epithelium, while Cdx2 mutant cells give rise to a succession of gastric-type tissue but never to a small intestine morphology. Our results indicate a difference in potency between forestomach and midgut precursor endodermal cells.

Animals↗

PubMed2003

X-inactivation patch size in human female tissue confounds the assessment of tumor clonality.

Most models of tumorigenesis assume that tumors are monoclonal in origin. This conclusion is based largely on studies using X chromosome-linked markers in females. One important factor, often ignored in such studies, is the distribution of X-inactivated cells in tissues. Because lyonization occurs early in development, many of the progeny of a single embryonic stem cell are grouped together in the adult, forming patches. As polyclonality can be demonstrated only at the borders of X-inactivation patches, the patch size is crucial in determining the chance of demonstrating polyclonality and hence the number of tumors that need to be examined to exclude polyclonality. Previously studies using X-linked genes such as glucose-6-phosphate dehydrogenase have been handicapped by the need to destroy the tissues to study the haplotypes of glucose-6-phosphate dehydrogenase [Fialkow, P.-J. (1976) Biochim. Biophys. Acta 458, 283-321] or to determine the restriction fragment length polymorphisms of X chromosome-linked genes [Vogelstein, B., Fearon, E. R., Hamilton, S. R. & Feinberg, A. P. (1985) Science 227, 642-645]. Here we visualize X-inactivation patches in human females directly. Results show that the patch size is relatively large in both the human colon and breast, confounding assessment of tumor clonality with traditional X-inactivation studies.

Adult↗

PubMed2003

Plastic adult stem cells: will they graduate from the school of hard knocks?

Notwithstanding the fact that adult bone marrow cell engraftment to epithelial organs seems a somewhat uncommon event, there is no doubt it does occur, and under appropriate conditions of a strong and positive selection pressure these cells will expand clonally and make a significant contribution to tissue replacement. Likewise, bone-marrow-derived cells can be amplified in vitro and differentiated into a multitude of tissues. These in essence are the goals of regenerative medicine using any source of stem cells, be it embryonic or adult. Despite such irrefutable evidence of what is possible, a veritable chorus of detractors of adult stem cell plasticity has emerged, some doubting its very existence, motivated perhaps by more than a little self-interest. The issues that have led to this state of affairs have included the inability to reproduce certain widely quoted data, one case where the apparent transdifferentiation was due to contamination of the donor tissue with haematopoietic cells and, most notoriously, extrapolating from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. While these issues need resolving, slamming this whole new field because not everything is crystal clear is not good science. The fact that a phenomenon is quite rare in no way mitigates against its very existence: asteroid collisions with the Earth are rare, but try telling the dinosaurs they do not occur! When such events do occur (transdifferentiation or collision), they certainly can make an impact.

Animals↗

PubMed2003

Uroplakin gene expression in normal human tissues and locally advanced bladder cancer.

The uroplakins are widely regarded as urothelium-specific markers of terminal urothelial cytodifferentiation. This study investigated the expression of the four uroplakin genes, UPIa, UPIb, UPII and UPIII, in a wide range of normal human tissues to determine tissue specificity and in advanced transitional cell carcinoma (TCC) to examine gene expression in primary and metastatic disease. In the urinary tract, all four uroplakins were expressed by urothelium and UPIII was also expressed by prostatic glandular epithelium. UPIa and UPII appeared to be urothelium-specific, but UPIb was detected in several non-urothelial tissues, including the respiratory tract, where it was associated with squamous metaplasia of tracheal and bronchial epithelia. The ten cases of primary TCC and corresponding lymph node metastases demonstrated that each uroplakin gene could be expressed at the mRNA level. No single uroplakin gene was expressed in all primary tumours or metastases, but 80% of the primary tumours and 70% of the lymph node metastases expressed at least one uroplakin gene. UPIII mRNA was often expressed in the absence of UPIII protein. These results confirm that in human tissues the expression of UPIa and UPII genes is highly specific to urothelium and suggest that the tight differentiation-restricted expression of uroplakin genes in normal urothelium is lost following malignant transformation.

Carcinoma, Transitional Cell↗

PubMed2003

Malignant phyllodes tumours show stromal overexpression of c-myc and c-kit.

Phyllodes tumours are fibroepithelial neoplasms of the breast, the stroma of which can undergo malignant progression to sarcoma. The frequency of malignant lesions varies in different series from 5% to 30%. The aim of this study was to elucidate potential molecular mechanisms in the progression to malignancy in phyllodes tumours. c-myc and c-kit were studied at the protein, RNA(c-myc only) and DNA level. We chose to study c-myc as we have previously shown that Wnt signalling is important in benign, but not malignant, phyllodes tumours. If c-myc is constitutively activated in malignant tumours, this may provide an explanation for why the Wnt pathway is no longer important in these tumours. c-kit is a membrane-bound tyrosine kinase receptor and overexpression is characteristic of gastrointestinal stromal tumours. A previous report suggested that this may also be the case in malignant phyllodes tumours, and we wished to confirm this. We assessed expression of c-myc and c-kit in 30 phyllodes tumours (10 malignant) using in situ hybridization (c-myc) and immunohistochemistry (c-myc and c-kit). 9/10 malignant tumours showed c-myc expression in the stroma, compared to 7/20 benign tumours (p = 0.006, Fisher's exact test). Stromal c-kit expression was found in 5/10 malignant tumours, compared to 1/20 benign tumours (p = 0.008, Fisher's exact test). One tumour had high-level amplification of c-myc, but we found no evidence of mutations of c-kit. We hypothesize that the overexpression of c-myc may drive stromal proliferation in malignant phyllodes tumours, and that c-kit overexpression contributes to the growth of these lesions. c-kit may also be a new therapeutic target in these tumours.

Breast Neoplasms↗

PubMed2003

Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast.

The aim of this study was to assess the expression of IGF-I and IGF-II in phyllodes tumours and fibroadenomas and to see if there is any correlation between nuclear beta-catenin expression and IGF-I and IGF-II expression in these tumours. In a previous study, it has been shown that Wnt signalling is important in the pathogenesis of phyllodes tumours of the breast. Epithelial Wnt5a overexpression and stromal Wnt2 overexpression were associated with abnormal, nuclear localization of beta-catenin in the stromal cells of these tumours. However, not all tumours with beta-catenin accumulation showed Wnt overexpression. One other possible cause of beta-catenin accumulation is overexpression of insulin-like growth factors (IGFs), as both IGF-I and IGF-II have been shown to stabilize beta-catenin. In this study, 30 fibroadenomas of the breast were assessed for beta-catenin expression using immunohistochemistry and the results were compared with previous data from 119 phyllodes tumours. In situ hybridization was used to assess IGF-I and IGF-II expression in 23 phyllodes tumours and 16 fibroadenomas. Nineteen phyllodes tumours (83%) showed widespread overexpression of IGF-II and 5/23 (22%) showed widespread overexpression of IGF-I. IGF-I expression correlated with nuclear beta-catenin staining in phyllodes tumours. Malignant phyllodes tumours showed no or little IGF-I expression. There was a degree of nuclear beta-catenin expression in the stroma (weak in 33%, moderate in 27%, and strong in 40%) in all fibroadenomas and nuclear beta-catenin staining correlated with IGF-I overexpression. Extensive IGF-II overexpression was also found in the majority of fibroadenomas (12/16). These results support the hypothesis that IGF-I and IGF-II overexpression may be important in the pathogenesis of fibroepithelial neoplasms of the breast and that IGF-I overexpression is likely to be contributing to the nuclear beta-catenin localization observed in the tumours.

Breast Neoplasms↗

PubMed2003

Bone marrow stem cells contribute to healing of the kidney.

A variety of recent studies support the existence of pathways, in adult humans and rodents, that allow adult stem cells to be surprisingly flexible in their differentiation repertoires. Termed plasticity, this property allows adult stem cells, assumed until now to be committed to generating a fixed range of progeny, on relocation to switch to make other specialized sets of cells appropriate to their new niche. Cells normally present within the bone marrow seem particularly flexible and are able to contribute usefully to many recipient organs. In studies of the liver, bone marrow-derived cells are seen with specialized structural and metabolic adaptations commensurate with their new locations, and these may be abundant, even sufficient, to rescue recipient mice from genetic defects and with evidence that they have proliferated in situ. In the kidney, several studies provide evidence for the presence of "reprogrammed" cells, but in most, it remains possible that cells arrive and redifferentiate but are no longer stem cells. Nevertheless, that appropriately differentiated cells are delivered deep within organs simply by injection of bone marrow cells should make us think differently about the way organs regenerate and repair. Migratory pathways for multipotential cells could be exploited to effect repairs using an individual's own stem cells, perhaps after gene therapy. This concept makes it clear that a transplanted organ would in time become affected by the genetic susceptibilities of the recipient, because of phenotypes that are expressed when trafficking cells incorporate and differentiate.

Animals↗

PubMed2003

Does bone marrow contain renal precursor cells?

In the past few years stem cells normally present within the bone marrow have been shown to have considerable plasticity in the repertoire of the cells that they produce. They are capable of producing specific lineages of cells not only of the blood, but also contribute usefully to lineages of other organs. In the kidney, studies in humans and rodents provide evidence for the presence of bone marrow-derived 're-programmed' cells, but it remains possible that the cells that arrive and re-differentiate are no longer stem cells (quiescent cells, not actively proliferating). Nevertheless, the fact that appropriately differentiated cells are delivered deep within the kidney simply by injection of bone marrow cells should make us think differently about the way these organs regenerate and repair. Migratory pathways for multipotential stem cells could be exploited to effect repair using an individual's own stem cells, perhaps after gene therapy. It is clear also that a transplanted organ would in time become affected by the genetic susceptibilities of the recipient, because of phenotypes that are expressed when trafficking cells engraft and differentiate.

Animals↗

PubMed2003

Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice.

Myofibroblasts are ubiquitous cells with features of both fibroblasts and smooth muscle cells. We suggest that the bone marrow can contribute to myofibroblast populations in a variety of tissues and that this is exacerbated by injury. To assess this, female mice were transplanted with male bone marrow and the male cells were tracked throughout the body and identified as myofibroblasts. Skin wounding and paracetamol administration were used to assess whether myofibroblast engraftment was modulated by damage. Following radiation injury, a proportion of myofibroblasts in the lung, stomach, esophagus, skin, kidney, and adrenal capsule were bone-marrow derived. In the lung, there was significantly greater engraftment following paracetamol administration (17% versus 41% p < 0.005). Bone-marrow-derived fibroblasts were also found. We suggest that bone marrow contributes to a circulating population of cells and, in the context of injury, these cells are recruited and contribute to tissue repair.

Actins↗

PubMed2002

Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease.

The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cell growth, adhesion, and protection from apoptosis. High plasma IGF-I levels predispose to prostate cancer, but there is no consensus regarding IGF1R expression in primary and metastatic prostate cancer. Recent studies in a human cell line and a mouse model suggest that metastatic prostate cancer cell detachment may be favored by impairing cadherin function via loss of expression of insulin receptor substrate-1 (IRS-1), the principal IGF1R docking molecule. This may be accompanied by PTEN mutation, reactivating a key antiapoptotic pathway, and by IGF1R down-regulation to prevent Shc-mediated differentiation. We studied IGF1R expression in 54 samples of primary prostate tissue including 44 archival and 10 prospectively collected biopsies. We performed semiquantitative immunostaining for the IGF1R, IRS-1, and PTEN, and in situ hybridization for IGF1R. The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium. There was a trend toward increased expression of IRS-1 in the malignant biopsies. We also measured IGF1R, IRS-1, and PTEN expression in 12 paired biopsies of primary prostate cancer and subsequent bone metastases. In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors. Three of these metastases also lacked significant PTEN staining, compatible with findings in the model systems described above. However, this pattern was relatively uncommon, and 8 of 12 cases expressed detectable IGF1R and IRS-1 in both primary and metastatic biopsies. These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology.

Adenocarcinoma↗

PubMed2002

The Wnt pathway, epithelial-stromal interactions, and malignant progression in phyllodes tumours.

In a previous study of phyllodes tumours, it has been shown that both the stroma and the epithelium can exhibit distinct molecular changes, suggesting that both are part of the neoplastic process. In view of this finding, it was decided to study stromal-epithelial interactions in these tumours by examining the Wnt-APC-beta-catenin pathway. Beta-catenin and cyclin D1 immunohistochemistry was performed on 119 phyllodes tumours. Eighty-six (72%) showed stromal nuclear beta-catenin localization and in 57% the staining was moderate or strong; however, of the eight malignant tumours in the series, seven showed absent or weak nuclear staining (p<0.025). In no tumour was nuclear beta-catenin staining seen in the epithelial component. Moderate or strong stromal cyclin D1 staining correlated with nuclear stromal beta-catenin staining (p<0.05). Forty-five of the tumours, including two malignant lesions, were screened for beta-catenin exon 3 mutations using SSCP and sequencing, but none was found. Loss of heterozygosity (LOH) of the marker D5S346 was used to infer APC mutation, but only one (benign) tumour showed LOH. Wnt2 and Wnt5a mRNA was localized by in situ hybridization in 13 cases (three malignant) chosen to reflect the different beta-catenin staining patterns. There was an association between strong nuclear beta-catenin staining of stromal cells and epithelial Wnt5a expression (p<0.0015). These data suggest that stromal proliferation in benign phyllodes tumours relies on abnormalities in the Wnt pathway which result not from mutation, but from Wnt5a expression in the epithelium. In the progression to malignancy, the stromal proliferation appears to become independent of the Wnt pathway and, presumably, of the epithelial component of these tumours.

Breast Neoplasms↗

PubMed2002

Hepatic stem cells.

The liver in an adult healthy body maintains a balance between cell gain and cell loss. Though normally proliferatively quiescent, hepatocyte loss such as that caused by partial hepatectomy, uncomplicated by virus infection or inflammation, invokes a rapid regenerative response to restore liver mass. This restoration of moderate cell loss and 'wear and tear' renewal is largely achieved by hepatocyte self-replication. Furthermore, hepatocyte transplants in animals have shown that a certain proportion of hepatocytes can undergo significant clonal expansion, suggesting that hepatocytes themselves are the functional stem cells of the liver. More severe liver injury can activate a potential stem cell compartment located within the intrahepatic biliary tree, giving rise to cords of bipotential so-called oval cells within the lobules that can differentiate into hepatocytes and biliary epithelial cells. A third population of stem cells with hepatic potential resides in the bone marrow; these haematopoietic stem cells can contribute to the albeit low renewal rate of hepatocytes, make a more significant contribution to regeneration, and even completely restore normal function in a murine model of hereditary tyrosinaemia. How these three stem cell populations integrate together to achieve a homeostatic balance is not known. This review focuses on two major aspects of liver stem cell biology: firstly, the identity of the liver stem cells, and secondly, their potential value in the treatment of major liver disease.

Animals↗

PubMed2002

The expression of E-cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients.

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with beta-catenin and gamma-catenin and APC mutations are believed to play a role in the altered levels of beta-catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E-cadherin and catenins in colorectal neoplasms and non-neoplastic mucosa from FAP patients. The expression and cellular distribution of E-cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non-neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E-cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E-cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non-neoplastic mucosa.

Adenomatous Polyposis Coli↗

PubMed2002

Adult stem cell plasticity.

Observations made in the last few years support the existence of pathways, in adult humans and rodents, that allow adult stem cells to be surprisingly flexible in their differentiation repertoires. Termed plasticity, this property allows adult stem cells, assumed, until now, to be committed to generating a fixed range of progeny, to switch, when they have been relocated, to make other specialized sets of cells appropriate to their new niche. Reprogramming of some adult stem cells can occur in vivo; the stem cells normally resident in bone marrow appear particularly flexible and are able to contribute usefully to multiple recipient organs. This process produces cells with specialized structural and metabolic adaptations commensurate with their new locations. In a few examples, the degree of support is sufficient to assist or even rescue recipient mice from genetic defects. Some studies provide evidence for the expansion of the reprogrammed cells locally, but in most it remains possible that cells arrive and redifferentiate, but are no longer stem cells. Nevertheless, the fact that appropriately differentiated cells are delivered deep within organs simply by injection of bone marrow cells should make us think differently about the way that organs regenerate and repair. Migratory pathways for stem cells in adult organisms may exist that could be exploited to effect repairs using an individual's own stem cells, perhaps after gene therapy. Logical extensions of this concept are that a transplanted organ would become affected by the genetic susceptibilities of the recipient, alleles that re-express themselves via marrow-derived stem cells, and that plasticity after bone marrow transplantation would also transfer different phenotypes, affecting important parameters such as susceptibility to long-term complications of diabetes, or the ability to metabolize drugs in the liver. This article reviews some of the evidence for stem cell plasticity in rodents and man.

Animals↗

PubMed2002

An introduction to stem cells.

1998 saw the publication of two papers describing the growth in vitro of human embryonic stem (ES) cells derived either from the inner cell mass (ICM) of the early blastocyst or the primitive gonadal regions of early aborted fetuses. Work on murine ES cells over many years had already established the amazing flexibility of ES cells, essentially able to differentiate into almost all cells that arise from the three germ layers. The realization of such pluripotentiality (see below) has, of course, resulted in the field of stem cell research going into overdrive, the establishment of many new biotechnology companies (http://www.stemcellresearchnew.com/catalog1677.html), and a genuine belief that stem cell research will deliver a revolution in terms of how we treat cardiovascular disease, neurodegenerative disease, cancer, diabetes, and the like. However, many people believe that early human embryos should be accorded the same status as any sentient being and thus their 'harvesting' for stem cells is morally unjustifiable. With this in mind, other sources of malleable stem cells have been sought. In the adult, organ formation and regeneration was thought to occur through the action of organ- or tissue-restricted stem cells (i.e. haematopoietic stem cells giving rise to all the cells of the blood, neural stem cells making neurons, astrocytes, and oligodendrocytes). However, it is now believed that stem cells from one organ system, for example the haematopoietic compartment can develop into the differentiated cells within another organ system, such as the liver, brain or kidney. Thus, certain adult stem cells may turn out be as malleable as ES cells and so also be useful in regenerative medicine. This brief overview summarizes the important attributes of tissue-based stem cells and clarifies the terms used.

Biomarkers↗