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Why only certain species can regenerate their appendages (e.g. tails and limbs) remains one of the biggest mysteries of nature. Unlike anuran tadpoles and salamanders, humans and other mammals cannot regenerate their limbs, but can only regrow lost digit tips under specific circumstances. Numerous hypotheses have been postulated to explain regeneration‐incompetency in mammals. By studying model organisms that show varying regenerative abilities, we now have more opportunities to uncover what contributes to regeneration‐incompetency and functionally test which perturbations restore appendage regrowth. Particularly, Xenopus laevis tail and limb, and mouse digit tip model systems exhibit naturally occurring variations in regenerative capacities. Here, we discuss major hypotheses that are suggested to contribute to regeneration‐incompetency, and how species with varying regenerative abilities reflect on these hypotheses. [ABSTRACT FROM AUTHOR]

In mammals, multi-tissue regeneration is largely restricted to the distal portion of the digit tip and involves the formation of a blastema, a transient, proliferating cell mass that reforms the diverse tissues of the digit. Historically little was known about the mammalian blastema but with recent advances in single cell transcriptomic approaches and genetic lineage tracing, a more precise understanding of this critical structure has begun to emerge. In this review we summarise the cellular mechanisms underlying adult mammalian digit tip regeneration. We posit that understanding how some mammals naturally regenerate complex tissues will lead to strategies for enhancing regenerative abilities in humans. [ABSTRACT FROM AUTHOR]

Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration. [ABSTRACT FROM AUTHOR]

Cellular senescence is an irreversible form of cell cycle arrest that has been linked to several pathological conditions. In particular, senescence can function as a tumor suppressor mechanism, but is also thought to contribute to organismal aging. Paradoxically however, through the secretion of various factors, collectively termed the senescence-associated secretory phenotype (SASP), senescent cells can also have tumor-promoting and tissue-remodeling functions. In addition, senescent cells can play beneficial roles in tissue repair and wound healing, and reconciling these contradictory features from an evolutionary standpoint has been challenging. Moreover, senescent cells had not previously been documented in non-pathological conditions. Recently however, 2 studies have identified cellular senescence as a programmed mechanism that contributes to tissue patterning and remodeling during normal embryonic development. These findings have significant implications for our understanding of cellular senescence and help to clarify the paradoxes and the evolutionary origin of this process. [ABSTRACT FROM PUBLISHER]

Summary: Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process. [Copyright &y& Elsevier]

Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra -expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single-cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb or digit Pdgfra -positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema-state genes and contribute to bone regeneration. Moreover, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a blastema state that enables cells from tissues such as bone to contribute to the regeneration of other mesenchymal tissues such as the dermis. • Pdgfra -expressing mesenchymal cells from uninjured digits establish the blastema • Adult digit tip regeneration is distinct from embryonic digit development • The blastema state is environmentally determined • The regenerative environment enables mesenchymal lineage plasticity Storer et al. use lineage tracing, single-cell RNA sequencing, and cell transplantation to define the transcriptional identity of the mesenchymal cells comprising the blastema and the major transitions during mammalian digit tip regeneration. The regenerative environment determines the adult blastema state and confers mesenchymal lineage flexibility. [ABSTRACT FROM AUTHOR]

Altered stem cell homeostasis is linked to organismal aging. However, the mechanisms involved remain poorly understood. Here we report novel alterations in hair follicle stem cells during skin aging, including increased numbers, decreased function, and an inability to tolerate stress. Performing high-throughput RNA sequencing on aging stem cells, cytokine arrays, and functional assays, we identify an age-associated imbalance in epidermal Jak-Stat signaling that inhibits stem cell function. Collectively, this study reveals a role for the aging epidermis in the disruption of cytokine and stem cell homeostasis, suggesting that stem cell decline during aging may be part of broader tumor-suppressive mechanisms. [ABSTRACT FROM AUTHOR]

Immature multipotent embryonic peripheral glial cells, the Schwann cell precursors (SCPs), differentiate into melanocytes, parasympathetic neurons, chromaffin cells, and dental mesenchymal populations. Here, genetic lineage tracing revealed that, during murine embryonic development, some SCPs detach from nerve fibers to become mesenchymal cells, which differentiate further into chondrocytes and mature osteocytes. This occurred only during embryonic development, producing numerous craniofacial and trunk skeletal elements, without contributing to development of the appendicular skeleton. Formation of chondrocytes from SCPs also occurred in zebrafish, indicating evolutionary conservation. Our findings reveal multipotency of SCPs, providing a developmental link between the nervous system and skeleton. [ABSTRACT FROM AUTHOR]

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) isa rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high- resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis. [ABSTRACT FROM AUTHOR]