Plasticity after allogeneic hematopoietic stem cell transplantation

AbstractThe postulated almost unlimited potential of transplanted hematopoietic stem cells (HSCs) to transdifferentiate into cell types that do not belong to the hematopoietic system denotes a complete paradigm shift of the hierarchical hemopoietic tree. In several studies during the last few years, donor cells have been identified in almost all recipient tissues after allogeneic HSC transplantation (HSCT), supporting the theory that any failing organ could be accessible to regenerative cell therapy. However, the putative potential ability of the stem cells to cross beyond lineage barriers has been questioned by other studies which suggest that hematopoietic cells might fuse with non-hematopoietic cells and mimic the appearance of transdifferentiation. Proof that HSCs have preserved the capacity to transdifferentiate into other cell types remains to be demonstrated. In this review, we focus mainly on clinical studies addressing plasticity in humans who underwent allogeneic HSCT. We summarize the published data on non-hematopoietic chimerism, donor cell contribution to tissue repair, the controversies related to the methods used to detect donor-derived non-hematopoietic cells and the functional impact of this phenomenon in diverse specific target tissues and organs.

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Purified murine hematopoietic stem cells function longer on nonirradiated W41/Wv than on +/+ irradiated stroma

Blood ◽

10.1182/blood.v81.6.1489.1489 ◽

1993 ◽

Vol 81 (6) ◽

pp. 1489-1496 ◽

Cited By ~ 5

Author(s):

F Vecchini ◽

KD Patrene ◽

SS Boggs

Keyword(s):

Stem Cells ◽

Wheat Germ ◽

Donor Cell ◽

Mouse Bone Marrow ◽

Hematopoietic Stem ◽

Cell Production ◽

Donor Cells ◽

Nonadherent Cell ◽

Specific Increase

Abstract Mouse bone marrow (BM) was separated into low-density, lineage- negative, wheat germ agglutinin-positive (WGA+), Rhodamine-123 bright (Rhbright) or dim (Rhdim) cells to obtain populations that were highly enriched for committed progenitors (Rhbright cells) or for more primitive stem cells (Rhdim). When 2,500 Rhbright or Rhdim cells were seeded onto 6-week-old irradiated (20 Gy) long-term BM cultures (LTBMC), the nonadherent cell production from Rhbright cells was transient and ended after 5 weeks. Production from Rhdim cells did not begin until week 3, peaked at week 5, and ended at week 8, when the irradiated stroma seemed to fail. Termination of cell production from Rhdim cells did not occur in nonirradiated LTBMC from W41/Wv mice. During peak nonadherent cell production, 25% to 30% of the cells in the nonirradiated LTBMC from W41/Wv mice had donor cell markers. Two approaches were tested to try to enhance the proportion or number of donor cells. Addition of Origen-HGF at the time of seeding Rhdim cells caused a nonspecific increase in both host and donor cell production, but a specific increase in production of donor cells was obtained by seeding the cultures at 2 weeks rather than 6 weeks. Limiting dilution of Rhdim cells gave the same frequency of wells producing cells on both irradiated +/+ and nonirradiated W41/Wv or W/Wv cultures.

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Purified murine hematopoietic stem cells function longer on nonirradiated W41/Wv than on +/+ irradiated stroma

Blood ◽

10.1182/blood.v81.6.1489.bloodjournal8161489 ◽

1993 ◽

Vol 81 (6) ◽

pp. 1489-1496

Author(s):

F Vecchini ◽

KD Patrene ◽

SS Boggs

Keyword(s):

Stem Cells ◽

Wheat Germ ◽

Donor Cell ◽

Mouse Bone Marrow ◽

Hematopoietic Stem ◽

Cell Production ◽

Donor Cells ◽

Nonadherent Cell ◽

Specific Increase

Mouse bone marrow (BM) was separated into low-density, lineage- negative, wheat germ agglutinin-positive (WGA+), Rhodamine-123 bright (Rhbright) or dim (Rhdim) cells to obtain populations that were highly enriched for committed progenitors (Rhbright cells) or for more primitive stem cells (Rhdim). When 2,500 Rhbright or Rhdim cells were seeded onto 6-week-old irradiated (20 Gy) long-term BM cultures (LTBMC), the nonadherent cell production from Rhbright cells was transient and ended after 5 weeks. Production from Rhdim cells did not begin until week 3, peaked at week 5, and ended at week 8, when the irradiated stroma seemed to fail. Termination of cell production from Rhdim cells did not occur in nonirradiated LTBMC from W41/Wv mice. During peak nonadherent cell production, 25% to 30% of the cells in the nonirradiated LTBMC from W41/Wv mice had donor cell markers. Two approaches were tested to try to enhance the proportion or number of donor cells. Addition of Origen-HGF at the time of seeding Rhdim cells caused a nonspecific increase in both host and donor cell production, but a specific increase in production of donor cells was obtained by seeding the cultures at 2 weeks rather than 6 weeks. Limiting dilution of Rhdim cells gave the same frequency of wells producing cells on both irradiated +/+ and nonirradiated W41/Wv or W/Wv cultures.

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Fibronectin and Its Receptors in Hematopoiesis

Cells ◽

10.3390/cells9122717 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2717

Author(s):

Franziska Wirth ◽

Alexander Lubosch ◽

Stefan Hamelmann ◽

Inaam A. Nakchbandi

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Matrix Protein ◽

Cell Types ◽

Extracellular Matrix Protein ◽

In Vivo Models ◽

Hematopoietic Stem ◽

Almost All

Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell niche produce the various isoforms of this protein. Fibronectin not only provides the cells a scaffold to bind to, but it also modulates their behavior by binding to receptors on the adjacent hematopoietic stem cells and stromal cells. These receptors, which include integrins such as α4β1, α9β1, α4β7, α5β1, αvβ3, Toll-like receptor-4 (TLR-4), and CD44, are found on the hematopoietic stem cell. Because the knockout of fibronectin is lethal during embryonal development and because fibronectin is produced by almost all cell types in mammals, the study of its role in hematopoiesis is difficult. Nevertheless, strong and direct evidence exists for its stimulation of myelopoiesis and thrombopoiesis using in vivo models. Other reviewed effects can be deduced from the study of fibronectin receptors, which showed their activation modifies the behavior of hematopoietic stem cells. Erythropoiesis was only stimulated under hemolytic stress, and mostly late stages of lymphocytic differentiation were modulated. Because fibronectin is ubiquitously expressed, these interactions in health and disease need to be taken into account whenever any molecule is evaluated in hematopoiesis.

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The Role of Collagen Type I on Hematopoietic and Mesenchymal Stem Cells Expansion and Differentiation

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.409.111 ◽

2011 ◽

Vol 409 ◽

pp. 111-116 ◽

Cited By ~ 6

Author(s):

Betül Çelebi ◽

Nicolas Pineault ◽

D. Mantovani

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Collagen Type ◽

Hematopoietic Cells ◽

Cell Types ◽

Collagen Type I ◽

Type I ◽

Hematopoietic Stem ◽

The Impact

The three dimensional scaffold of the bone marrow (BM) niches is composed of various elements including extracellular matrix proteins and cell types, such as collagen type I (Col I) and stroma cells. Interaction of stem cells with their microenvironment is important for their regulation. In the marrow, Col I is mostly localized in the endosteal regions. The objective of this work was to investigate the role of Col I in the regulation of Hematopoietic Stem Cells (HSC) and Mesenchymal Stem Cells (MSC) growth. Col I was extracted from rat tail tendons and its purity confirmed. Human BM MSCs and umbilical cord blood (UCB) CD34+cells were used as Stem Cell sources. MSCs were cultured in medium with serum while CB CD34+cells were cultured without serum with cytokines. The impact of increasing concentrations of Col I (0-50 µg mL-1for coating) on the growth of Hematopoietic Progenitor Cells (HPC) and MSCs was investigated by cytometry, microscopy and clonogenic progenitor assays. Only a minority of CD34+cells expressed the Col I receptor α2β1prior to culture, while the opposite was observed when hematopoietic cells were placed in culture. Col I coated surfaces reduced the expansion of hematopoietic cells by 25% compared to control, while expansions of myeloid and MK progenitors were either unchanged or negatively affected by Col I, respectively. The differentiation of HPCs was also affected on Col I as demonstrated by differences in the frequencies of various cell lineages, such as CD34+cells, megakaryocytes (MK), erythrocytes and others. In contrast to HPCs, Col I surfaces increased MSCs proliferation but had little impact on osteoblasts derived from MSCs. Taken together, this study provides new insights into the regulatory activities of Col I on Stem Cells residing in the marrow.

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Dynamic integration of enteric neural stem cells in ex vivo organotypic colon cultures

Scientific Reports ◽

10.1038/s41598-021-95434-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Georgina Navoly ◽

Conor J. McCann

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Organotypic Culture ◽

Ex Vivo ◽

Donor Cell ◽

Colonic Tissue ◽

Cell Therapies ◽

Enteric Ganglia ◽

Donor Cells

AbstractEnteric neural stem cells (ENSC) have been identified as a possible treatment for enteric neuropathies. After in vivo transplantation, ENSC and their derivatives have been shown to engraft within colonic tissue, migrate and populate endogenous ganglia, and functionally integrate with the enteric nervous system. However, the mechanisms underlying the integration of donor ENSC, in recipient tissues, remain unclear. Therefore, we aimed to examine ENSC integration using an adapted ex vivo organotypic culture system. Donor ENSC were obtained from Wnt1cre/+;R26RYFP/YFP mice allowing specific labelling, selection and fate-mapping of cells. YFP+ neurospheres were transplanted to C57BL6/J (6–8-week-old) colonic tissue and maintained in organotypic culture for up to 21 days. We analysed and quantified donor cell integration within recipient tissues at 7, 14 and 21 days, along with assessing the structural and molecular consequences of ENSC integration. We found that organotypically cultured tissues were well preserved up to 21-days in ex vivo culture, which allowed for assessment of donor cell integration after transplantation. Donor ENSC-derived cells integrated across the colonic wall in a dynamic fashion, across a three-week period. Following transplantation, donor cells displayed two integrative patterns; longitudinal migration and medial invasion which allowed donor cells to populate colonic tissue. Moreover, significant remodelling of the intestinal ECM and musculature occurred upon transplantation, to facilitate donor cell integration within endogenous enteric ganglia. These results provide critical evidence on the timescale and mechanisms, which regulate donor ENSC integration, within recipient gut tissue, which are important considerations in the future clinical translation of stem cell therapies for enteric disease.

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The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22052472 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2472

Author(s):

Carl Randall Harrell ◽

Valentin Djonov ◽

Vladislav Volarevic

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Immune Cells ◽

Tissue Repair ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Multipotent Stem Cells ◽

Tissue Repair And Regeneration ◽

Almost All ◽

And Function

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.

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Histone Acetyltransferases and Stem Cell Identity

Cancers ◽

10.3390/cancers13102407 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2407

Author(s):

Ruicen He ◽

Arthur Dantas ◽

Karl Riabowol

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Epigenetic Modification ◽

Cell Types ◽

Histone Acetyltransferases ◽

Specific Cell ◽

Cell Fates ◽

Cell Identity ◽

Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

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First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽

10.1007/s10456-021-09783-9 ◽

2021 ◽

Author(s):

Giovanni Canu ◽

Christiana Ruhrberg

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Fetal Liver ◽

Cell Types ◽

Yolk Sac ◽

Vascular Endothelial ◽

Hematopoietic Stem ◽

Close Proximity ◽

Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

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Designer blood: creating hematopoietic lineages from embryonic stem cells

Blood ◽

10.1182/blood-2005-09-3621 ◽

2006 ◽

Vol 107 (4) ◽

pp. 1265-1275 ◽

Cited By ~ 51

Author(s):

Abby L. Olsen ◽

David L. Stachura ◽

Mitchell J. Weiss

Keyword(s):

Stem Cells ◽

Es Cells ◽

Embryonic Stem ◽

Basic Research ◽

Cell Types ◽

Patient Specific ◽

Es Cell ◽

Blood Disorders ◽

Hematopoietic Stem

Embryonic stem (ES) cells exhibit the remarkable capacity to become virtually any differentiated tissue upon appropriate manipulation in culture, a property that has been beneficial for studies of hematopoiesis. Until recently, the majority of this work used murine ES cells for basic research to elucidate fundamental properties of blood-cell development and establish methods to derive specific mature lineages. Now, the advent of human ES cells sets the stage for more applied pursuits to generate transplantable cells for treating blood disorders. Current efforts are directed toward adapting in vitro hematopoietic differentiation methods developed for murine ES cells to human lines, identifying the key interspecies differences in biologic properties of ES cells, and generating ES cell-derived hematopoietic stem cells that are competent to repopulate adult hosts. The ultimate medical goal is to create patient-specific and generic ES cell lines that can be expanded in vitro, genetically altered, and differentiated into cell types that can be used to treat hematopoietic diseases.

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