Hematopoietic stem cells: the paradigmatic tissue-specific stem cell

The recent prospective isolation of a wide variety of somatically derived stem cells has affirmed the notion that homeostatic maintenance of most tissues and organs is mediated by tissue-specific stem and progenitor cells and fueled enthusiasm for the use of such cells in strategies aimed at repairing or replacing damaged, diseased, or genetically deficient tissues and organs. Hematopoietic stem cells (HSCs) are arguably the most well-characterized tissue-specific stem cell, with decades of basic research and clinical application providing not only a profound understanding of the principles of stem cell biology, but also of its potential pitfalls. It is our belief that emerging stem cell fields can benefit greatly from an understanding of the lessons learned from the study of HSCs. In this review we discuss some general concepts regarding stem cell biology learned from the study of HSCs with a highlight on recent work pertaining to emerging topics of interest for stem cell biology.     

Hematopoietic stem cells in the intact and regenerating adult mouse liver

It was shown by the splenic colonies method that hematopoietic stem cells are present in the intact liver of adult CBA mice. Their number increases during regeneration of the liver after partial hepatectomy.N. K. Kol'tsov Institute of Developmental Biology, Academy of Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. P. Avtsyn.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 2, pp. 209–210, February, 1977.     

Hematopoietic stem cells

This review focuses on the genomics of mouse hematopoiesis but also draws parallels to other systems and discusses issues common to the analysis of rare populations such as stem cells. As examples from the mouse blood forming system are used to illustrate several points, the authors first give a brief introduction to mouse hematopoiesis as a model system. We review the multiple microarray analyses that have been performed on various mouse hematopoietic subpopulations and comment on both technical and biological aspects of such experiments. The concept of stemness is discussed, and the importance of biological function of gene products, protein-protein interactions and molecular pathways highlighted. Finally, the authors discuss some major unresolved issues in hematopoiesis and discuss the potential uses of future microarray analysis as well as other genomic and functional approaches that might prove useful to further our understanding of hematopoiesis and other stem cell systems.     

Hematopoietic stem cells.

Recent studies indicate that hematopoietic stem cells that provide long-term reconstitution can be separated from more mature hematopoietic cells that provide radioprotection and short-term repopulation. With these findings it is now possible to design assays that will specifically measure long-term repopulating stem cells, as well as to develop culture systems that can be used to analyze the effects of known and putative novel cytokines on their growth and differentiation.     

Hematopoietic stem cell transplantation procedures

Hematopoietic stem cell transplantation has been utilized for the treatment of severe autoimmune diseases following the results of experimental studies and of coincidental diseases. While allogeneic transplantation is still being explored, autologous transplantation is the procedure most frequently utilized worldwide. The rationale for its utilization consists in its powerful immunosuppressive effect, but immune modulation polarized towards tolerance is also postulated. The mobilization of stem and progenitor cells from the marrow and the various conditioning regimens derive from the experience with hematologic malignancies. The greatest possible reduction of transplant-related-mortality and of the autoimmune aggression are being actively pursued. Here, the main procedural modalities will be analyzed and discussed.     

Hematopoietic stem cell transplantation procedures

Hematopoietic stem cell transplantation has been utilized for the treatment of severe autoimmune diseases following the results of experimental studies and of coincidental diseases. While allogeneic transplantation is still being explored, autologous transplantation is the procedure most frequently utilized worldwide. The rationale for its utilization consists in its powerful immunosoppressive effect, but immune modulation polarized towards tolerance is also postulated.

The mobilization of stem and progenitor cells from the marrow and the various conditioning regimens derive from the experience with hematologic malignancies. The greatest possible reduction of trasplant-related-mortality and of the autoimmune aggression are being actively pursued. Here, the main procedural modalities will be analyzed and discussed.     

Hematopoietic stem cells in elderly people

Marrow stem cells from old and young donors have often been compared by measuring concentration and numbers of CFU-S in mice. However, little information is available on hematopoietic stem cells in elderly people. This present study was undertaken to investigate age-associated changes in the concentrations of granulocyte-macrophage progenitor cell (CFU-C) and erythrocyte progenitor cell (CFU-E) in human bone marrow. We examined CFU-C from 101 subjects and CFU-E from 26 subjects by age, ranging from 28 to 95 years, and found there was no difference in the concentration of CFU-C but a slight decrease of the concentration in CFU-E in elderly subjects.     

Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche

Crosstalk between hematopoietic stem cells (HSCs) and the cells comprising the niche is critical for maintaining stem cell activities. Yet little evidence supports the concept that HSCs regulate development of the niche. Here, the ability of HSCs to directly regulate endosteal development was examined. Marrow was isolated 48 hours after "stressing" mice with a single acute bleed or from control nonstressed animals. "Stressed" and "nonstressed" HSCs were cocultured with bone marrow stromal cells to map mesenchymal fate. The data suggest that HSCs are able to guide mesenchymal differentiation toward the osteoblastic lineage under basal conditions. HSCs isolated from animals subjected to an acute stress were significantly better at inducing osteoblastic differentiation in vitro and in vivo than those from control animals. Importantly, HSC-derived bone morphogenic protein 2 (BMP-2) and BMP-6 were responsible for these activities. Furthermore, significant differences in the ability of HSCs to generate a BMP response following stress were noted in aged and in osteoporotic animals. Together these data suggest a coupling between HSC functions and bone turnover as in aging and in osteoporosis. For the first time, these results demonstrate that HSCs do not rest passively in their niche. Instead, they directly participate in bone formation and niche activities. Disclosure of potential conflicts of interest is found at the end of this article.     

Hematopoietic stem and progenitor cell trafficking

Migration of hematopoietic stem cells (HSCs) is essential during embryonic development and throughout adult life. During embryogenesis, trafficking of HSCs is responsible for the sequential colonization of different hematopoietic organs by blood-producing cells. In adulthood, circulation of HSCs maintains homeostasis of the hematopoietic system and participates in innate immune responses. HSC trafficking is also crucial in clinical settings such as bone marrow (BM) and stem cell transplantation. This review provides an overview of the molecular and cellular signals that control and fine-tune trafficking of HSCs and hematopoietic progenitor cells in embryogenesis and during postnatal life. We also discuss the potential clinical utility of therapeutic approaches to modulate HSC trafficking in patients.     

Opioid receptors localize to the external granular cell layer of the developing human cerebellum.

The distribution of opioid receptors in the developing human cerebellum was determined by tissue autoradiography using [3H]naloxone. In infants, opioid receptors were heavily concentrated in the external granular layer, a matrix of germinal cells, and were substantially less concentrated in the internal granular layer, differentiating progeny of external granular cells. In the mature internal granular layer of the child and adult, opioid receptors were negligible. Thus, in the human cerebellum, opioid receptors localize to a population of germinal cells and are negligible in their mature progeny. These data support the idea that endogenous opioids play a role in human brain development and may function as receptor-mediated growth factors. The cerebellum provides a model site to examine abnormal opioid effects upon human brain development, particularly in infants exposed to narcotics in utero.     

Hematopoietic stem cells and their niche

Recent evidence indicates that osteoblasts are crucial components of the particular microenvironments, or niches, for hematopoietic stem cells (HSCs) in adult bone marrow (BM). Stem cells persist in an immature state within the BM. The quiescence of HSCs is controlled dynamically by the signaling of receptors-ligands and cell-adhesion molecules. In this review, the characteristics of HSCs in the niche are discussed. The understanding of the relationship between normal and cancer stem cells and their niches should lead to the development of new strategies directed toward regeneration medicine and cancer therapeutics.     

Hematopoietic stem cells for cancer immunotherapy

Hematopoietic stem cells (HSCs) provide an attractive target for immunotherapy of cancer and leukemia by the introduction of genes encoding T-cell receptors (TCRs) or chimeric antigen receptors (CARs) directed against tumor-associated antigens. HSCs engraft for long-term blood cell production and could provide a continuous source of targeted anti-cancer effector cells to sustain remissions. T cells produced de novo from HSCs may continuously replenish anti-tumor T cells that have become anergic or exhausted from ex vivo expansion or exposure to the intratumoral microenvironment. In addition, transgenic T cells produced in vivo undergo allelic exclusion, preventing co-expression of an endogenous TCR that could mis-pair with the introduced TCR chains and blunt activity or even cause off-target reactivity. CAR-engineered HSCs may produce myeloid and natural killer cells in addition to T cells expressing the CAR, providing broader anti-tumor activity that arises quickly after transplant and does not solely require de novo thymopoiesis. Use of TCR- or CAR-engineered HSCs would likely require cytoreductive conditioning to achieve long-term engraftment, and this approach may be used in clinical settings where autologous HSC transplant is being performed to add a graft-versus-tumor effect. Results of experimental and preclinical studies performed to date are reviewed.     

Migration of dorsal aorta mesenchymal stem cells induced by mouse embryonic circulation

Mesenchymal stem cells (MSCs) represent powerful tools for regenerative medicine for their differentiation and migration capacity. However, ontogeny and migration of MSCs in mammalian mid‐gestation conceptus is poorly understood. We identified canonical MSCs in the mouse embryonic day (E) 11.5 dorsal aorta (DA). They possessed homogenous immunophenotype (CD45^?CD31^?Flk‐1^?CD44⁺CD29⁺), expressed perivascular markers (α‐SMA⁺NG2⁺PDGFRβ⁺PDGFRα⁺), and had tri‐lineage differentiation potential (osteoblasts, adipocytes, and chondrocytes). Of interest, MSCs were also detected in E12.5–E13.5 embryonic circulation, 24 hr later than in DA, suggesting migration like hematopoietic stem cells. Functionally, E12.5 embryonic blood could trigger efficient migration of DA‐MSCs through platelet‐derived growth factor (PDGF) receptor‐, transforming growth factor‐beta receptor‐, but not basic fibroblast growth factor receptor‐mediated signaling. Moreover, downstream JNK and AKT signaling pathway played important roles in embryonic blood‐ or PDGF‐mediated migration of DA‐derived MSCs. Taken together, these results revealed that clonal MSCs developed in the mouse DA. More importantly, the embryonic circulation, in addition to its conventional transporting roles, could modulate migration of MSC during early embryogenesis. Developmental Dynamics, 2011. © 2010 Wiley‐Liss, Inc.