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Malcolm R Alison

Publications and source records attributed to Malcolm R Alison.

At least 19 recordsLinked to original sources
PubMed2007

Cellular pathways to beta-cell replacement.

In the twenty-first century, diabetic patients are likely to be one of the major beneficiaries from the advancement of regenerative medicine through cellular therapies. Though the existence of a specific self-renewing stem cell within the pancreas is still far from clear, a surprising variety of cells within the pancreas can differentiate towards a beta-cell phenotype: ductular cells, periductular mesenchymal cells and beta-cells themselves can all give rise to new beta-cells. Extra-pancreatic adult somatic stem cells, in particular, those originating from bone marrow may also be capable of differentiating to beta-cells, though equally well the beneficial effects of bone marrow cells may reside in their contribution to the damaged islet vasculature. Forced expression of the beta-cell-specific transcription factor Pdx1 in hepatocytes also holds promise as a therapeutic strategy to increase insulin levels in diabetic individuals. Embryonic stem (ES) cells are clearly another possible source for generating beta-cells, but ES cells are beyond the scope of this review, which focuses on adult stem and progenitor cells capable of producing beta-cells. Despite considerable endeavour, we still have much to learn in the field of pancreatic regeneration prior to any clinically applicable therapy based upon adult stem cells.

Animals↗
PubMed2007

Copper deprivation in rats induces islet hyperplasia and hepatic metaplasia in the pancreas.

BACKGROUND INFORMATION: Prolonged copper deprivation in rats followed by refeeding with a normal diet has previously been used to induce the appearance of hepatocyte-like cells in the pancreas, but the effects on islet size and morphology have not been determined. RESULTS: In the present study we investigated the distribution of pancreatic alpha- and beta-cells and of hepatocytes in adult rats fed a copper-deficient diet followed by refeeding with a normal diet. Immunohistochemical staining for insulin and glucagon showed that the islets of the copper-deficient group were up to 2.4 times larger in mass compared with controls. The islets were disorganized, with alpha-cells found in multiple layers at the periphery of the islet and sometimes deep in the core. Isolated alpha- and beta-cells were also found in increased numbers in the ductular system. Copper deprivation caused almost complete ablation of the acinar cells, and refeeding induced adipogenesis, acinar regeneration and hepatocyte-like cells. Ductular proliferation and nerve hyperplasia were also present. The hepatocytes tended to be associated with islets or with ducts, rather than with residual pancreatic exocrine tissue. CONCLUSIONS: These data show that copper deficiency in rats, as well as inducing the appearance of hepatocytes, is capable of causing islet hyperplasia.

Animals↗
PubMed2006

Stem cell plasticity and tumour formation.

Stem cell plasticity refers to the ability of certain stem cells to switch lineage determination and generate unexpected cell types. This review applies largely to bone marrow cells (BMCs), which appear to contribute positively to the regeneration of several damaged non-haematopoietic tissues. This beneficial effect on regeneration may be a direct result of BMCs giving rise to organ parenchymal cells. Alternatively, it could be due to BMCs fusing with existing parenchymal cells, or providing paracrine growth factor support, or contributing to neovascularisation. In the context of oncology, BMC derivation of the tumour stroma and vasculature has profound biological and therapeutic implications, and there are several examples of carcinomas seemingly being derived from BMCs.

Animals↗
PubMed2006

Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants.

RATIONALE: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated. OBJECTIVES: This study analyzes whether circulating, bone marrow-derived, fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans. METHODS: The occurrence of in situ microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post-bone marrow transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by short tandem repeat-polymerase chain reaction-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromosomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2). MEASUREMENTS AND MAIN RESULTS: The bronchiolitis obliterans lesions of all 12 lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean, 32%). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients also displayed clear in situ microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%). CONCLUSIONS: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially in other organs.

Adult↗
PubMed2006

Bone marrow-derived stromal cells express lineage-related messenger RNA species.

Evidence has emerged that bone marrow cells have a greater degree of plasticity than previously thought. However, there has been a call to establish proof that these bone marrow-derived cells function appropriately in their new environment. We have already shown that the bone marrow contributes to myofibroblasts in multiple organs and that this is exacerbated by injury and occurs in a mouse tumor model. Here, we provide evidence that these cells are functioning appropriately by showing that bone marrow-derived myofibroblasts are expressing mRNA for the alpha(1) chain of type I (pro)collagen using a new customized technique. This provides evidence that the bone marrow-tumor stroma axis is functionally relevant and may therefore subsequently be exploited to develop new strategies for anticancer therapy.

Animals↗
PubMed2006

The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice.

After liver injury, parenchymal regeneration occurs through hepatocyte replication. However, during regenerative stress, oval cells (OCs) and small hepatocyte like progenitor cells (SHPCs) contribute to the process. We systematically studied the intra-hepatic and extra-hepatic sources of liver cell replacement in the hepatitis B surface antigen (HBsAg-tg) mouse model of chronic liver injury. Female HBsAg-tg mice received a bone marrow (BM) transplant from male HBsAg-negative mice, and half of these animals received retrorsine to block indigenous hepatocyte proliferation. Livers were examined 3 and 6 months post-BM transplantation for evidence of BM-derived hepatocytes, OCs, and SHPCs. In animals that did not receive retrorsine, parenchymal regeneration occurred through hepatocyte replication, and the BM very rarely contributed to hepatocyte regeneration. In mice receiving retrorsine, 4.8% of hepatocytes were Y chromosome positive at 3 months, but this was frequently attributable to cell fusion between indigenous hepatocytes and donor BM, and their frequency decreased to 1.6% by 6 months, as florid OC reactions and nodules of SHPCs developed. By analyzing serial sections and reconstructing a 3-dimensional map, continuous streams of OCs could be seen that surrounded and entered deep into the nodules of SHPCs, connecting directly with SHPCs, suggesting a conversion of OCs into SHPCs. In conclusion, during regenerative stress, the contribution to parenchymal regeneration from the BM is minor and frequently attributable to cell fusion. OCs and SHPCs are of intrinsic hepatic origin, and OCs can form SHPC nodules.

Animals↗
PubMed2006

Bone marrow and tumour stroma: an intimate relationship.

In recent years the bone marrow has become recognized as a potential source of cells for non-haematopoietic wound healing, in some instances demonstrating surprising plasticity in providing new epithelial cells. On the other hand, the contribution of bone marrow derived cells to fibrosis and blood vessel formation is more widely acknowledged. Tumour stroma has a vital role to play in determining cancer growth and spread, and there is a growing realization that the bone marrow has a significant input into this desmoplastic response. This review focuses on the contribution of bone marrow cells to tumour stroma, highlighting the bone marrow as a potential new portal through which to direct anti-tumour therapies.

Animals↗
PubMed2006

The bone marrow functionally contributes to liver fibrosis.

BACKGROUND & AIMS: Bone marrow (BM) cells may transdifferentiate into or fuse with organ parenchymal cells. BM therapy shows promise in murine models of cirrhosis, and clinical trials of bone marrow stem cell therapy for organ healing are underway. However, the BM may contribute to scar-forming myofibroblasts in various organs including the liver. We have studied this axis of regeneration and scarring in murine models of cirrhosis, including an assessment of the temporal and functional contribution of the BM-derived myofibroblasts. METHODS: Female mice were lethally irradiated and received male BM transplants. Carbon tetrachloride or thioacetamide was used to induce cirrhosis. BM-derived cells were tracked through in situ hybridization for the Y chromosome. BM transplants from 2 strains of transgenic mice were used to detect intrahepatic collagen production. RESULTS: In the cirrhotic liver, the contribution of BM to parenchymal regeneration was minor (0.6%); by contrast, the BM contributed significantly to hepatic stellate cell (68%) and myofibroblast (70%) populations. These BM-derived cells were found to be active for collagen type 1 transcription in 2 independent assays and could influence the fibrotic response to organ injury. These BM-derived myofibroblasts did not occur through cell fusion between BM-derived cells and indigenous hepatic cells but, instead, originated largely from the BM's mesenchymal stem cells. CONCLUSIONS: The BM contributes functionally and significantly to liver fibrosis and is a potential therapeutic target in liver fibrosis. Clinical trials of BM cell therapy for liver regeneration should be vigilant for the possibility of enhanced organ fibrosis.

Animals↗
PubMed2005

Proliferation of bone marrow-derived cells contributes to regeneration after folic acid-induced acute tubular injury.

Studies of tissue from recipients of bone marrow transplantation or organ allograft suggest that bone marrow-derived cells (BMDC) may differentiate into a variety of nonhematologic tissues, including renal tubular epithelium. The aims of this study were to examine whether BMDC contribute to recovery after acute renal injury and to assess the effects of cytokine mobilization on regeneration. Female mice (6 wk old) were lethally irradiated and transplanted with male bone marrow (BM) cells and later assigned into control, folic acid-treatment, and folic acid-treatment with granulocyte-colony stimulating factor (G-CSF), and control with G-CSF. Tritiated thymidine was given 1 h before death. Kidney sections were stained for a tubular epithelial marker, Y chromosome (in situ hybridization), periodic acid-Schiff staining, and subjected to autoradiography. Renal tubular epithelial cells in S-phase were scored as female (indigenous) or male (BM-derived). This is the first report to show that BMDC can respond by engrafting the renal tubules and undergo DNA synthesis after acute renal injury. BMDC contributed to the renal tubular epithelial cell population, although most (90%) renal tubular regeneration came from female indigenous cells. Some evidence was found for cell fusion between indigenous renal tubular cells and BMDC, but this was infrequent and the significance and consequences of cell fusion in the kidney are unresolved. G-CSF treatment nearly doubled the frequency of thymidine-labeled BM-derived tubular cells and might facilitate the recovery of renal tubular epithelium.

Animals↗
PubMed2005

Bone marrow cells engraft within the epidermis and proliferate in vivo with no evidence of cell fusion.

In adults, bone marrow-derived cells (BMDC) can contribute to the structure of various non-haematopoietic tissues, including skin. However, the physiological importance of these cells is unclear. This study establishes that bone marrow-derived epidermal cells are proliferative and, moreover, demonstrates for the first time that BMDC can localize to a known stem cell niche: the CD34-positive bulge region of mouse hair follicles. In addition, engraftment of bone marrow cells into the epidermis is significantly increased in wounded skin, bone marrow-derived keratinocytes can form colonies in the regenerating epidermis in vivo, and the colony-forming capacity of these cells can be recapitulated in vitro. In some tissues this apparent plasticity is attributed to differentiation, and in others to cell fusion. Evidence is also provided that bone marrow cells form epidermal keratinocytes without undergoing cell fusion. These data suggest a functional role for bone marrow cells in epidermal regeneration, entering known epidermal stem cell niches without heterokaryon formation.

Animals↗
PubMed2005

A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts.

BACKGROUND & AIMS: Bone marrow (BM) cells form differentiated adult lineages within nonhematopoietic tissues, with a heightened propensity with increasing regenerative pressure dictated by disease. We have previously shown that BM cells engraft into the gut and contribute substantially to the subepithelial intestinal myofibroblast population in the lamina propria. To investigate the reparative capacity of BM in inflammatory bowel disease (IBD), a well-established model of experimental colitis was used. METHODS: Lethally irradiated female mice were rescued by a BM transplant from male donors. Colitis was induced 6 weeks posttransplantation by injection of trinitrobenzene sulfonic acid (TNBS), and tissues were analyzed 1-14 days later. Donor-derived cells were detected by in situ hybridization using a Y chromosome-specific probe, and their phenotype was determined by immunohistochemistry. RESULTS: TNBS-induced colitis was manifest as patchy lesions that increased in severity between days 1 and 8, and the mucosa gradually regenerated between days 8 and 14. The contribution of BM to intestinal myofibroblasts was significantly increased in regions of colitis compared with noninflamed regions. Furthermore, BM-derived endothelial cells, pericytes, and vascular smooth muscle cells were frequently interspersed throughout blood vessels, suggesting that these cells facilitate angiogenesis in tissue repair, substantiated by a significant increase in the incidence of BM-derived vascular smooth muscle cells in colitic compared with noninflamed regions. Blood vessels formed entirely from BM-derived cells were also seen, suggesting a role for BM in neovasculogenesis. CONCLUSIONS: Our data show that BM contributes to multiple intestinal cell lineages in colitis, with an important function in tissue regeneration and vasculogenesis after injury.

Animals↗
PubMed2005

The expression of minichromosome maintenance protein-2 in normal and abnormal megakaryocytes and comparison with the proliferative marker Ki-67.

The minichromosome maintenance (Mcm) and Cdc6 proteins are important regulators of eucaryotic DNA replication. In most normal tissues, a similar proportion of cells express Mcm-2 and Ki-67. The present study showed that in both normal and abnormal states, the proportion of megakaryocytes expressing Mcm-2 is roughly seven times as many as those that express Ki-67. This is likely to be related to the process of endomitosis and endoreduplication. We also demonstrated that a significantly lower proportion of megakaryocytes in myelodysplastic syndrome express Mcm-2. These findings provide new insights into megakaryocyte biology.

Bone Marrow↗
PubMed2005

Liver stem cells: implications for hepatocarcinogenesis.

Numerous studies point to the fact that liver tumors are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal mucosa and epidermis, in which a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, though it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover the existence of bipotential hepatic progenitor cells (HPCs), along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Irrespective of which target cell is involved, cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, any proliferative cell in the liver can be susceptible to neoplastic transformation. Thus, hepatocytes are implicated in many instances of HCC, direct injury to the biliary epithelium implicates cholangiocytes in some cases of CC, whereas HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that HPC proliferation may be merely a bystander effect of this toxicity. An indepth discussion of causes of cancer in the liver are beyond the scope of this review, but infectious agents (e.g., hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus [HBV]), but in also causing chronic inflammation (hepatitis C virus [HCV] and HBV). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors, and DNA-damaging agents (reactive oxygen and nitrogen species produced to fight infection), will lead to permanent genetic changes in proliferating cells. The upregulation of the transcription factor nuclear factor kappaB (NF-kappaB) in transformed hepatocytes, through the paracrine action of tumor necrosis factor-alpha from neighboring endothelia and inflammatory cells, may be critical for tumor progression given the mitogenic and anti-apoptotic properties of proteins encoded by many of NF-kappaB's target genes.

Animals↗
PubMed2004

Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts.

The role of myofibroblasts in tissue repair and fibrosis is well documented, but the source of these myofibroblasts is unclear. There is evidence of a circulating population of fibrocytes that can home to areas of injury and contribute to myofibroblast populations. Previously, we have shown that the bone marrow is a source of myofibroblasts for many tissues including the gut, lung, and kidney and that this phenomenon is exacerbated by injury. We now show that the bone marrow can contribute to myofibroblast and fibroblast populations in tumor stroma in a mouse model of pancreatic insulinoma. Mice transgenic for the rat insulin promoter II gene linked to the large-T antigen of SV40 (RIPTag) develop solid beta-cell tumors of the pancreas. Approximately 25% of myofibroblasts in these pancreatic tumors were donor-derived, and these were concentrated toward the edge of the tumor. Thus, the development of tumor stroma is at least in part a systemic response that may ultimately yield methods of targeting new therapy.

Actins↗
PubMed2004

A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.

BACKGROUND & AIMS: Myofibroblasts of bone marrow origin have recently been found in a number of parenchymal organs such as the gut and kidney. We have analyzed the origin of myofibroblasts within fibrotic liver in 2 scenarios: (1) 7 male patients (hepatitis B; hepatitis B and D; Wilson's disease; hepatitis B, D, and C; and 3 with hepatitis C) who received liver transplants from female donors and subsequently developed liver fibrosis and (2) a female patient who received a bone marrow transplant from a male donor and subsequently developed hepatitis C-induced cirrhosis. METHODS: Through the use of in situ hybridization for the Y chromosome, we have tracked male cells of extrahepatic origin. The phenotype of these male cells was examined by immunohistochemistry using a panel of antibodies against alpha-smooth muscle actin (alpha SMA), vimentin, fibulin-2, and leukocyte common antigen (CD45). Confocal microscopy was performed to confirm the location of the Y chromosome probe within the myofibroblast nuclei. RESULTS: Significant numbers of Y chromosome-positive cells in fibrotic areas were found to be positive for alpha-SMA, vimentin, and fibulin-2 and negative for CD45, thus having a myofibroblast phenotype. In the liver transplant cases, 6.8%-22.2% of alpha-SMA-positive myofibroblasts contained the Y chromosome. In the female recipient of a bone marrow transplant from a male donor, 12.4% of the myofibroblasts were Y chromosome positive, indicating a bone marrow origin. CONCLUSIONS: There is a significant contribution to liver cirrhosis in humans from extrahepatically derived myofibroblasts in liver disease of diverse etiology.

Actins↗
PubMed2004

Adult stem cell plasticity: will engineered tissues be rejected?

The dogma that adult tissue-specific stem cells remain committed to supporting only their own tissue has been challenged; a new hypothesis, that adult stem cells demonstrate plasticity in their repertoires, is being tested. This is important because it seems possible that haematopoietic stem cells, for example, could be exploited to generate and perhaps deliver cell-based therapies deep within existing nonhaematopoietic organs. Much of the evidence for plasticity derives from histological studies of tissues from patients or animals that have received grafts of cells or whole organs, from a donor bearing (or lacking) a definitive marker. Detection in the recipient of appropriately differentiated cells bearing the donor marker is indicative of a switch in phenotype of a stem cell or a member of a transit amplifying population or of a differentiated cell. In this review, we discuss evidence for these changes occurring but do not consider the molecular basis of cell commitment. In general, the extent of engraftment is low but may be increased if tissues are damaged. In model systems of liver regeneration, the repeated application of a selection pressure increases levels of engraftment considerably; how this occurs is unclear. Cell fusion plays a part in regeneration and remodelling of the liver, skeletal muscle and even regions of the brain. Genetic disease may be amenable to some forms of cell therapy, yet immune rejection will present challenges. Graft-vs.-host disease will continue to present problems, although this may be avoided if the cells were derived from the recipient or they were tolerized. Despite great expectations for cellular therapies, there are indications that attempts to replace missing proteins could be confounded simply by the development of specific immunity that rejects the new phenotype.

Adult↗