You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: Feedback, Lineages and Self-Organizing Morphogenesis}
Article:
Abstract:
Feedback regulation of cell lineage progression plays an important role in tissue size homeostasis, but whether such feedback also plays an important role in tissue morphogenesis has yet to be explored. Here we use mathematical modeling to show that a particular feedback architecture in which both positive and negative diffusible signals act on stem and/or progenitor cells leads to the appearance of bistable or bi-modal growth behaviors, ultrasensitivity to external growth cues, local growth-driven budding, self-sustaining elongation, and the triggering of self-organization in the form of lamellar fingers. Such behaviors arise not through regulation of cell cycle speeds, but through the control of stem or progenitor self-renewal. Even though the spatial patterns that arise in this setting are the result of interactions between diffusible factors with antagonistic effects, morphogenesis is not the consequence of Turing-type instabilities.
Introduction:
Diffusible molecules, such as morphogens, growth factors, cytokines and chemokines, play many important roles in solid tissues, among which are conveying positional information, coordinating proliferation with differentiation, and enabling collective responses to disturbances[1–6]. Less clear, however, is the importance of diffusible signals in orchestrating the morphogenesis of solid tissues—i. e. the formation of three-dimensional structures such as sacs, tubes, sheets, buds and branches. Typically, the events of morphogenesis are described in terms of intrinsic cellular behaviors, such as cell migration[7], localized changes in cell shape[8–12], differential proliferation[13, 14], regulated cleavage plane orientation[15–18], differential cell adhesion[19], and mechanical force production[20]. How much of a role long-range diffusible cues play in organizing these processes is poorly understood. Recent mathematical modeling has suggested that the ability of diffusible molecules to spontaneously create large-scale spatial patterns( “Turing patterns”[21, 22]) might drive branching morphogenesis in the lung[23]. Turing patterns have also been implicated in digit morphogenesis in vertebrate limbs[24]. As the necessary conditions for Turing patterning are relatively restrictive—for example, pairs of factors that differ greatly in their diffusivity are required—how commonly this mechanism is exploited in morphogenesis remains to be seen. Here we identify a different mechanism by which diffusible signals can drive morphogenesis—not one based on creating patterns that act upstream of tissue growth or cell movement, but on regulating cell lineage progression, so that patterns arise directly out of tissue growth and cell displacement. As we describe below, such interactions can create large-scale spatial structure, and generate sharply-demarcated tissue forms, both spontaneously and in response to graded and/or transient extrinsic cues. Underlying such behavior is a negative feedback loop that has primarily been studied for its role in size homeostasis of continually self-renewing tissues[2, 25–27]. The basis of this mechanism is the production of diffusible molecules by differentiated cells that act upon stem or progenitor cells to decrease the probability of self-renewal, and increase the probability of differentiation. In muscle, for example, such feedback comes from GDF8/myostatin[28, 29], whereas in the olfactory epithelium the related molecules GDF11 and activin play an analogous role[30, 31]. Such feedback causes stem cell populations to automatically coordinate their behaviors so that net renewal is maintained at exactly 50%—the value required for homeostasis[25, 32]. Feedback of this type also produces steady states that are “perfectly” robust, insofar as tissue size is maintained at a set-point independent of initial conditions, cell cycle speed, or rates of cell turnover[25]. During development, the regulation of tissue and organ growth is less a matter of achieving homeostasis, than of efficiently arriving at a correct final size and shape( i. e., morphogenesis). Indeed, for the many organs in which cell turnover is non-existent or negligible in the adult, a controlled growth trajectory during development is the only possible function of feedback regulation. Fortunately, mathematical modeling shows that negative feedback control of self-renewal, the same strategy that achieves robust steady states in tissues that turn over, can also achieve nearly perfectly robust final states for tissues that do not turn over[25]. Indeed, feedback molecules such as GDF8, GDF11, myostatin and other renewal-inhibiting factors are often highly expressed during development. Yet, interestingly, such molecules are often co-expressed with other diffusible molecules that have exactly the opposite effect on stem and progenitors cells—promoting renewal at the expense of differentiation. In the developing olfactory epithelium, for example, the same cells that produce GDF11, which inhibits the renewal of progenitor cells, also produce FGF ligands that stimulate renewal of the same cells[33]. In muscle, production of renewal-inhibiting GDF8 is similarly accompanied by production of renewal-stimulating FGFs[34]. In other tissues, pairs of co-expressed renewal-promoting and-inhibiting factors include Wnts and BMPs[35]; HGF and TGFβ[36]; and PTHrP and FGF[37]. Mixing positive and negative feedback might at first seem counterproductive, but it is well known that countervailing feedback loops—if they are non-linear and operate on sufficiently well-separated temporal or spatial scales—can give rise to interesting dynamic or spatially-dynamic behaviors. Indeed, Turing patterns may be seen as a special case of this general phenomenon. Here we show that the simultaneous positive and negative feedback regulation of cell renewal by diffusible signals tends naturally to lead to the spontaneous emergence of spatially dynamic behaviors, which manifest as sharply localized differences in net growth. We mathematically define the conditions required for underlying phenomena such as bistability, ultrasensitivity and spatial self-organization to arise in such systems, and show how they can be used to drive the formation of induced or spontaneous bulges, buds and fingers( the basic building blocks of many types of morphogenesis). We further show that even though such phenomena arise out of the opposing interactions of diffusible factors, the patterns that arise are not Turing patterns. Rather, pattern formation is driven by the coupling between tissue growth and the inherent ultrasensitivity of the underlying system, and not by intrinsic differences in the spatial ranges of action of diffusible positive and negative signals.
Discussion:
Here we show that feedback regulation of stem or progenitor cell self-renewal can lead to growth bistability or bimodality, with ultrasensitive switching between high and low( or zero) growth states. A necessary condition for such behavior is the simultaneous presence of saturable positive and negative feedback. Exactly which lineage stage serves as the source of feedback signals appears less important than the fact that the strength of positive feedback must significantly exceed that of negative. When this type of arrangement is implemented in space, the resulting ultrasensitivity can lead to sharply demarcated growth differences that may be self-sustaining, producing bulges, buds or fingers that could serve as building blocks for morphogenesis. Such behavior typifies self-organization, in that the forms and sizes of buds and fingers that emerge reflect the parameters and structure of the feedback system, not the details of the stimuli that initiated them. Because we only explored here a small number of very simple lineage architectures, boundary conditions, and sources of noise; and we considered only a limited number of mechanical constraints on cell behavior, it is possible that the diversity of forms that could be generated through lineage feedback is much greater than shown in this study. Even for the relatively simple buds and fingers that we observe here, it will be difficult to determine precisely what system characteristics are the primary determinants of shape and size. This is because the decision by cells whether or not to enter a “growth leap” regime at any point in time and space will be influenced not only by the parameters of the system, but also by the gradients of diffusible factors that are set up by dividing and differentiated cells nearby. So far, the idea that lineage negative feedback( i. e. negative feedback regulation of self-renewal) plays a major physiological role has come mainly from studies of size control in self-renewing tissues, although the molecular nature of the relevant feedback factors is known in only a subset of such cases[25, 27, 28, 30, 43]. In many of these tissues, positive feedback factors—secreted molecules that promote cell renewal—have been clearly identified, yet there has been little speculation about the purpose of such feedback. Here we raise the possibility that positive feedback is useful because it creates the potential for growth-driven, self-organizing morphogenesis. In support of this view, we note several in vivo reports of phenomena analogous to those discussed here, including growth bistability/bimodality, feedback ultrasensitivity, and feedback-regulated morphogenesis. For example, in the mouse olfactory epithelium( OE), a reduction in the strength of FGF signaling( due to loss of Fgf8[44]), or an increase in the strength of GDF11/activin signaling( due to loss of Foxg1, which regulates responsiveness to GDF11 and activin[38]), can lead not just to a smaller OE, but to a complete absence of tissue( agenesis). Agenesis due to loss of Foxg1 can be rescued by inactivation of Gdf11, consistent with idea that a critical threshold ratio of positive-to-negative feedback determines whether a zero or non-zero growth state is achieved[38]. Interestingly, inactivation of even a single allele of Gdf11 in Foxg1 mutant animals restores the OE to full thickness, supporting the idea that growth state is an ultrasensitive function of feedback strength, as in Fig 1F. In mouse muscle, evidence for growth bistability can be found in transplantation experiments in which myofiber-associated satellite cells are allowed to re-populate injured muscle[45]. In such experiments the transplanted cells, which are FGF2-treated prior to transplantation, trigger an abnormally high rate of myoblast proliferation and differentiation, which becomes sustained, without further intervention, for years. As in the OE, muscle cell lineages are known to be controlled by mixed negative and positive feedback through secreted factors myostatin[28] and FGFs[46]. Triggered high rates of proliferation and differentiation that self-sustain for long periods are also observed in pathological skin conditions, such as psoriasis, acanthosis nigricans, and keloid formation[47–49]. Psoriasis is a particularly interesting example, because the excessive keratinocyte stem cell proliferation that characterizes psoriatic lesions typically occurs in domains that are sharply juxtaposed with normal skin, for reasons that are not yet understood. Ultrasensitivity that arises from a mix of intrinsic positive and negative lineage feedback could easily account for such sharply demarcated growth differences, as illustrated in Figs 4 and 5. Interestingly, therapeutic resolution of psoriatic lesions typically occurs only when stem cells are ablated below some threshold level[50], exactly what the lineage models presented here predict for a population that becomes “stuck” in a high growth state due to endogenous positive feedback. In acanthosis nigricans, which often occurs as a consequence of type II diabetes[48, 51], the epidermis thickens due to the presence of deeply folded stem cell layers, producing structures much like those observed in Fig 8. It is thought that high insulin levels interact with insulin-like growth factor-1 receptors to inhibit epidermal differentiation, i. e. insulin acts as an exogenous signal that boosts P[52]. In Figs 4–8, just such a signal can clearly act as a trigger of budding and fingering. Of course, fingered growth also occurs in normal tissues, as exemplified by the palisades of Vogt of the corneal limbus; lingual papillae, hair follicles, and even intestinal crypts, which initially develop as downgrowths from a smooth epithelial lining[53–56]. The roles played by diffusible positive or negative factors in the morphogenesis of these structures are incompletely understood, although in several cases the existence of both positive and negative feedback has been documented[55, 57]. Although these examples support the view that interesting, spatially dynamic phenomena do arise in vivo as a result of mixed positive and negative lineage feedback, the extent to which the morphogenesis that occurs during normal development relies upon such phenomena remains to be investigated. Some developmental phenomena do bear an intriguing superficial resemblance to observations made here. For example, vertebrate tailbud elongation proceeds through outgrowth, at a relatively constant rate, of a constant-width, finger-like projection, with self-renewing cells concentrated at the tip[58, 59], much like what is observed in Fig 7. Moreover, tailbud outgrowth is known to be driven by high concentrations, at the growing tip, of renewal-promoting FGF[60, 61], and terminated by differentiation-promoting retinoic acid, a diffusible factor that is both exogenously and endogenously provided, and acts in an ultrasensitive fashion to extinguish growth[61]. Obviously, feedback regulation of lineage progression is only one of many morphogenetic mechanisms at the disposal of developing tissues. Processes such as regulated cell cycle progression, directed cell migration, cell sorting, and active mechanical deformation clearly play important roles as well[e. g. 7, 17–20, 62–64]. What the present study elucidates are some of the advantages of lineage feedback-driven morphogenesis. These include the ability to specify spatial structure using the same molecules that regulate tissue homeostasis; the ability to coordinate the behaviors of cells over reasonably large spatial ranges; and the ability to create structure through self-organization, i. e. to form borders and boundaries spontaneously without the need for templates or pre-patterns.
A large variety of mechanisms have been proposed to explain how the cells of solid tissues work together to produce distinctive structures such as buds , branches , sacs and tubes . Here we identify a novel mechanism that emerges directly out of the processes that cells use to control proliferation and maintain overall tissue sizes . In particular , we focus on the diffusible molecules that regulate lineage progression—the decision by dividing cells either to renew themselves or produce cells of a more differentiated type . When such molecules are produced by cells at specific lineage stages , they create feedback circuits , and positive and negative lineage feedback circuits are often observed together in the same tissue . Here we show that the combination of positive and negative lineage feedback can lead to the emergence of patterned growth from which sharply-demarcated buds and fingers readily emerge , either spontaneously or in response to transient external signals . We show that the types of behaviors that emerge , and the conditions under which they do so , depend strongly on the relative strengths of positive and negative feedback .