The TNF and TNF receptor superfamilies: integrating mammalian biology.

Haematopoietic stem cells (HSCs) are a subset of bone marrow cells that are capable of self-renewal and of forming all types of blood cells (multi-potential). However, the HSC 'niche'--the in vivo regulatory microenvironment where HSCs reside--and the mechanisms involved in controlling the number of adult HSCs remain largely unknown. The bone morphogenetic protein (BMP) signal has an essential role in inducing haematopoietic tissue during embryogenesis. We investigated the roles of the BMP signalling pathway in regulating adult HSC development in vivo by analysing mutant mice with conditional inactivation of BMP receptor type IA (BMPRIA). Here we show that an increase in the number of spindle-shaped N-cadherin+CD45- osteoblastic (SNO) cells correlates with an increase in the number of HSCs. The long-term HSCs are found attached to SNO cells. Two adherens junction molecules, N-cadherin and beta-catenin, are asymmetrically localized between the SNO cells and the long-term HSCs. We conclude that SNO cells lining the bone surface function as a key component of the niche to support HSCs, and that BMP signalling through BMPRIA controls the number of HSCs by regulating niche size.

/pdf/identification-of-the-haematopoietic-stem-cell-niche-and-3oyrls2rg6.pdf

Identification of the haematopoietic stem cell niche and control of the niche size

Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell

The repair of wounds is one of the most complex biological processes that occur during human life. After an injury, multiple biological pathways immediately become activated and are synchronized to respond. In human adults, the wound repair process commonly leads to a non-functioning mass of fibrotic tissue known as a scar. By contrast, early in gestation, injured fetal tissues can be completely recreated, without fibrosis, in a process resembling regeneration. Some organisms, however, retain the ability to regenerate tissue throughout adult life. Knowledge gained from studying such organisms might help to unlock latent regenerative pathways in humans, which would change medical practice as much as the introduction of antibiotics did in the twentieth century.

/pdf/wound-repair-and-regeneration-1rzgi7hifn.pdf

Wound repair and regeneration

Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche

Involvement of follicular stem cells in forming not only the follicle but also the epidermis.

Using double labeling techniques, we studied the replication of corneal epithelial stem cells that reside exclusively in the limbal zone, and their progeny transit amplifying cells. We show that corneal epithelial stem cells can be induced to enter DNA synthesis by wounding and by TPA. We demonstrate the existence of a hierarchy of TA cells; those of peripheral cornea undergo at least two rounds of DNA synthesis before they become post-mitotic, whereas those of central cornea are capable of only one round of division. However, the cell cycle time of these TA cells can be shortened and the number of times these TA cells can replicate is increased in response to wounding. These results thus demonstrate three strategies of epithelial repair: (i) stem cell replication, (ii) the unleashing of additional rounds of cell proliferation that remain as an untapped reserve under normal circumstances, and (iii) enhancement of TA cell proliferation via a shortening of the cycling time.

http://sun-lab.med.nyu.edu/files_private/sun-lab/attachments/1998.JCS.Lehrer.pdf

Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jlts.2000.9745

Successful reversal of recalcitrant hepatic allograft rejection by photopheresis

Novel multimodality biologic response modifier therapy, including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa cutaneous T-cell lymphoma

The use of photochemotherapy for the treatment of cutaneous T-cell lymphoma (CTCL) was first reported by Gilchrest et al in 1976 Oral 8-methoxypsoralen (8MOP) was administered to patients with early-stage disease, followed by photoactivation with ultraviolet-A irradiation to the skin This technique, referred to as PUVA, has since become a mainstay of therapy for CTCL and other inflammatory skin conditions In the early 1980s PUVA was modified for the treatment of CTCL patients with more advanced disease Subsequent to oral 8MOP administration, whole blood was collected and enriched for white blood cells The leukocyte-enriched population was then irradiated with UVA and returned to the patient intravenously This technique was referred to as extracorporeal photopheresis (ECP) and represented the first ‘‘systemic’’ form of PUVA therapy In 1987 Edelson published the first report documenting the use of ECP in the treatment of patients with erythrodermic CTCL A 73% overall clinical response rate was reported, with a median survival time of 62 months from the onset of erythroderma In comparison to historical controls, ECP was associated with improved survival and decreased morbidity among patients with similar clinical characteristics In 1988, ECP was approved by the US Food and Drug Administration (FDA) for the treatment of CTCL Aside from its proven effectiveness in the management of CTCL, ECP has been shown to be of clinical benefit in the treatment of systemic sclerosis, cutaneous graft-versus-host disease, systemic lupus erythromatosis (SLE), allograft rejection, and potentially other autoimmune conditions Numerous studies have addressed the utility of ECP for CTCL both as a monotherapy and in combination with other biologic response modifying agents Over the past decade, we have observed higher clinical response rates among patients treated with a multimodality approach consisting of one or more biologic response modifying agents in combination with ECP The biologic response modifiers utilized have been shown to exert potent immunomodulatory effects with the ability to enhance cell-mediated antitumor immunity Since the year 2000, with the use of novel combinations of therapy, including interferon gamma, bexarotene, and skin-directed PUVA, along with ECP, we have achieved a greater than 90% clinical response rate among patients treated with this approach

Michael S. Lehrer

Papers

Involvement of follicular stem cells in forming not only the follicle but also the epidermis.

Strategies of epithelial repair: modulation of stem cell and transit amplifying cell proliferation.

Successful reversal of recalcitrant hepatic allograft rejection by photopheresis

Novel multimodality biologic response modifier therapy, including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa cutaneous T-cell lymphoma

Extracorporeal photopheresis and multimodality immunomodulatory therapy in the treatment of cutaneous T-cell lymphoma.